Investigating the Broad Matrix-Gate Network in the Mitochondrial ADP/ATP Carrier through Molecular Dynamics Simulations

<!DOCTYPE html> <html lang="en" xmlns:og="http://ogp.me/ns#" xmlns:fb="https://www.facebook.com/2008/fbml"> <head> <meta charset="utf-8"> <meta http-equiv="X-UA-Compatible" content="IE=edge,chrome=1"> <meta content="mdpi" name="sso-service" /> <meta content="width=device-width, initial-scale=1.0" name="viewport" /> <title>Investigating the Broad Matrix-Gate Network in the Mitochondrial ADP/ATP Carrier through Molecular Dynamics Simulations</title><link rel="stylesheet" href="https://pub.mdpi-res.com/assets/css/font-awesome.min.css?eb190a3a77e5e1ee?1739526160"> <link rel="stylesheet" href="https://pub.mdpi-res.com/assets/css/jquery.multiselect.css?f56c135cbf4d1483?1739526160"> <link rel="stylesheet" href="https://pub.mdpi-res.com/assets/css/chosen.min.css?d7ca5ca9441ef9e1?1739526160"> <link rel="stylesheet" href="https://pub.mdpi-res.com/assets/css/main2.css?6398b1425402cd8f?1739526160"> <link rel="mask-icon" href="https://pub.mdpi-res.com/img/mask-icon-128.svg?c1c7eca266cd7013?1739526160" color="#4f5671"> <link rel="apple-touch-icon" sizes="180x180" href="https://pub.mdpi-res.com/icon/apple-touch-icon-180x180.png?1739526160"> <link rel="apple-touch-icon" sizes="152x152" href="https://pub.mdpi-res.com/icon/apple-touch-icon-152x152.png?1739526160"> <link rel="apple-touch-icon" sizes="144x144" href="https://pub.mdpi-res.com/icon/apple-touch-icon-144x144.png?1739526160"> <link rel="apple-touch-icon" sizes="120x120" href="https://pub.mdpi-res.com/icon/apple-touch-icon-120x120.png?1739526160"> <link rel="apple-touch-icon" sizes="114x114" href="https://pub.mdpi-res.com/icon/apple-touch-icon-114x114.png?1739526160"> <link rel="apple-touch-icon" sizes="76x76" href="https://pub.mdpi-res.com/icon/apple-touch-icon-76x76.png?1739526160"> <link rel="apple-touch-icon" sizes="72x72" href="https://pub.mdpi-res.com/icon/apple-touch-icon-72x72.png?1739526160"> <link rel="apple-touch-icon" sizes="57x57" href="https://pub.mdpi-res.com/icon/apple-touch-icon-57x57.png?1739526160"> <link rel="apple-touch-icon" href="https://pub.mdpi-res.com/icon/apple-touch-icon-57x57.png?1739526160"> <link rel="apple-touch-icon-precomposed" href="https://pub.mdpi-res.com/icon/apple-touch-icon-57x57.png?1739526160"> <link rel="manifest" href="/manifest.json"> <meta name="theme-color" content="#ffffff"> <meta name="application-name" content=" "/> <link rel="apple-touch-startup-image" href="https://pub.mdpi-res.com/img/journals/molecules-logo-sq.png?8600e93ff98dbf14"> <link rel="apple-touch-icon" href="https://pub.mdpi-res.com/img/journals/molecules-logo-sq.png?8600e93ff98dbf14"> <meta name="msapplication-TileImage" content="https://pub.mdpi-res.com/img/journals/molecules-logo-sq.png?8600e93ff98dbf14"> <link rel="stylesheet" href="https://pub.mdpi-res.com/assets/css/jquery-ui-1.10.4.custom.min.css?80647d88647bf347?1739526160"> <link rel="stylesheet" href="https://pub.mdpi-res.com/assets/css/magnific-popup.min.css?04d343e036f8eecd?1739526160"> <link rel="stylesheet" href="https://pub.mdpi-res.com/assets/css/xml2html/article-html.css?230b005b39af4260?1739526160"> <style> h2, #abstract .related_suggestion_title { } .batch_articles a { color: #000; } a, .batch_articles .authors a, a:focus, a:hover, a:active, .batch_articles a:focus, .batch_articles a:hover, li.side-menu-li a { } span.label a { color: #fff; } #main-content a.title-link:hover, #main-content a.title-link:focus, #main-content div.generic-item a.title-link:hover, #main-content div.generic-item a.title-link:focus { } #main-content #middle-column .generic-item.article-item a.title-link:hover, #main-content #middle-column .generic-item.article-item a.title-link:focus { } .art-authors a.toEncode { color: #333; font-weight: 700; } #main-content #middle-column ul li::before { } .accordion-navigation.active a.accordion__title, .accordion-navigation.active a.accordion__title::after { } .accordion-navigation li:hover::before, .accordion-navigation li:hover a, .accordion-navigation li:focus a { } .relative-size-container .relative-size-image .relative-size { } .middle-column__help__fixed a:hover i, } input[type="checkbox"]:checked:after { } input[type="checkbox"]:not(:disabled):hover:before { } #main-content .bolded-text { } #main-content .hypothesis-count-container { } #main-content .hypothesis-count-container:before { } .full-size-menu ul li.menu-item .dropdown-wrapper { } .full-size-menu ul li.menu-item > a.open::after { } #title-story .title-story-orbit .orbit-caption { #background: url('/img/design/000000_background.png') !important; background: url('/img/design/ffffff_background.png') !important; color: rgb(51, 51, 51) !important; } #main-content .content__container__orbit { background-color: #000 !important; } #main-content .content__container__journal { color: #fff; } .html-article-menu .row span { } .html-article-menu .row span.active { } .accordion-navigation__journal .side-menu-li.active::before, .accordion-navigation__journal .side-menu-li.active a { color: rgba(0,124,127,0.75) !important; font-weight: 700; } .accordion-navigation__journal .side-menu-li:hover::before , .accordion-navigation__journal .side-menu-li:hover a { color: rgba(0,124,127,0.75) !important; } .side-menu-ul li.active a, .side-menu-ul li.active, .side-menu-ul li.active::before { color: rgba(0,124,127,0.75) !important; } .side-menu-ul li.active a { } .result-selected, .active-result.highlighted, .active-result:hover, .result-selected, .active-result.highlighted, .active-result:focus { } .search-container.search-container__default-scheme { } nav.tab-bar .open-small-search.active:after { } .search-container.search-container__default-scheme .custom-accordion-for-small-screen-link::after { color: #fff; } @media only screen and (max-width: 50em) { #main-content .content__container.journal-info { color: #fff; } #main-content .content__container.journal-info a { color: #fff; } } .button.button--color { } .button.button--color:hover, .button.button--color:focus { } .button.button--color-journal { position: relative; background-color: rgba(0,124,127,0.75); border-color: #fff; color: #fff !important; } .button.button--color-journal:hover::before { content: ''; position: absolute; top: 0; left: 0; height: 100%; width: 100%; background-color: #ffffff; opacity: 0.2; } .button.button--color-journal:visited, .button.button--color-journal:hover, .button.button--color-journal:focus { background-color: rgba(0,124,127,0.75); border-color: #fff; color: #fff !important; } .button.button--color path { } .button.button--color:hover path { fill: #fff; } #main-content #search-refinements .ui-slider-horizontal .ui-slider-range { } .breadcrumb__element:last-of-type a { } #main-header { } #full-size-menu .top-bar, #full-size-menu li.menu-item span.user-email { } .top-bar-section li:not(.has-form) a:not(.button) { } #full-size-menu li.menu-item .dropdown-wrapper li a:hover { } #full-size-menu li.menu-item a:hover, #full-size-menu li.menu.item a:focus, nav.tab-bar a:hover { } #full-size-menu li.menu.item a:active, #full-size-menu li.menu.item a.active { } #full-size-menu li.menu-item a.open-mega-menu.active, #full-size-menu li.menu-item div.mega-menu, a.open-mega-menu.active { } #full-size-menu li.menu-item div.mega-menu li, #full-size-menu li.menu-item div.mega-menu a { border-color: #9a9a9a; } div.type-section h2 { font-size: 20px; line-height: 26px; font-weight: 300; } div.type-section h3 { margin-left: 15px; margin-bottom: 0px; font-weight: 300; } .journal-tabs .tab-title.active a { } </style> <link rel="stylesheet" href="https://pub.mdpi-res.com/assets/css/slick.css?f38b2db10e01b157?1739526160"> <meta name="title" content="Investigating the Broad Matrix-Gate Network in the Mitochondrial ADP/ATP Carrier through Molecular Dynamics Simulations"> <meta name="description" content="The mitochondrial ADP/ATP carrier (AAC) exports ATP and imports ADP through alternating between cytosol-open (c-) and matrix-open (m-) states. The salt bridge networks near the matrix side (m-gate) and cytosol side (c-gate) are thought to be crucial for state transitions, yet our knowledge on these networks is still limited. In the current work, we focus on more conserved m-gate network in the c-state AAC. All-atom molecular dynamics (MD) simulations on a variety of mutants and the CATR-AAC complex have revealed that: (1) without involvement of other positive residues, the charged residues from the three Px[DE]xx[KR] motifs only are prone to form symmetrical inter-helical network; (2) R235 plays a determinant role for the asymmetry in m-gate network of AAC; (3) R235 significantly strengthens the interactions between H3 and H5; (4) R79 exhibits more significant impact on m-gate than R279; (5) CATR promotes symmetry in m-gate mainly through separating R234 from D231 and fixing R79; (6) vulnerability of the H2-H3 interface near matrix side could be functionally important. Our results provide new insights into the highly conserved yet variable m-gate network in the big mitochondrial carrier family." > <link rel="image_src" href="https://pub.mdpi-res.com/img/journals/molecules-logo.png?8600e93ff98dbf14" > <meta name="dc.title" content="Investigating the Broad Matrix-Gate Network in the Mitochondrial ADP/ATP Carrier through Molecular Dynamics Simulations"> <meta name="dc.creator" content="Shihao Yao"> <meta name="dc.creator" content="Boyuan Ma"> <meta name="dc.creator" content="Qiuzi Yi"> <meta name="dc.creator" content="Min-Xin Guan"> <meta name="dc.creator" content="Xiaohui Cang"> <meta name="dc.type" content="Article"> <meta name="dc.source" content="Molecules 2022, Vol. 27, Page 1071"> <meta name="dc.date" content="2022-02-05"> <meta name ="dc.identifier" content="10.3390/molecules27031071"> <meta name="dc.publisher" content="Multidisciplinary Digital Publishing Institute"> <meta name="dc.rights" content="http://creativecommons.org/licenses/by/3.0/"> <meta name="dc.format" content="application/pdf" > <meta name="dc.language" content="en" > <meta name="dc.description" content="The mitochondrial ADP/ATP carrier (AAC) exports ATP and imports ADP through alternating between cytosol-open (c-) and matrix-open (m-) states. The salt bridge networks near the matrix side (m-gate) and cytosol side (c-gate) are thought to be crucial for state transitions, yet our knowledge on these networks is still limited. In the current work, we focus on more conserved m-gate network in the c-state AAC. All-atom molecular dynamics (MD) simulations on a variety of mutants and the CATR-AAC complex have revealed that: (1) without involvement of other positive residues, the charged residues from the three Px[DE]xx[KR] motifs only are prone to form symmetrical inter-helical network; (2) R235 plays a determinant role for the asymmetry in m-gate network of AAC; (3) R235 significantly strengthens the interactions between H3 and H5; (4) R79 exhibits more significant impact on m-gate than R279; (5) CATR promotes symmetry in m-gate mainly through separating R234 from D231 and fixing R79; (6) vulnerability of the H2-H3 interface near matrix side could be functionally important. Our results provide new insights into the highly conserved yet variable m-gate network in the big mitochondrial carrier family." > <meta name="dc.subject" content="ADP/ATP carrier" > <meta name="dc.subject" content="mitochondrial carrier family" > <meta name="dc.subject" content="transporter" > <meta name="dc.subject" content="molecular dynamics simulation" > <meta name ="prism.issn" content="1420-3049"> <meta name ="prism.publicationName" content="Molecules"> <meta name ="prism.publicationDate" content="2022-02-05"> <meta name ="prism.volume" content="27"> <meta name ="prism.number" content="3"> <meta name ="prism.section" content="Article" > <meta name ="prism.startingPage" content="1071" > <meta name="citation_issn" content="1420-3049"> <meta name="citation_journal_title" content="Molecules"> <meta name="citation_publisher" content="Multidisciplinary Digital Publishing Institute"> <meta name="citation_title" content="Investigating the Broad Matrix-Gate Network in the Mitochondrial ADP/ATP Carrier through Molecular Dynamics Simulations"> <meta name="citation_publication_date" content="2022/1"> <meta name="citation_online_date" content="2022/02/05"> <meta name="citation_volume" content="27"> <meta name="citation_issue" content="3"> <meta name="citation_firstpage" content="1071"> <meta name="citation_author" content="Yao, Shihao"> <meta name="citation_author" content="Ma, Boyuan"> <meta name="citation_author" content="Yi, Qiuzi"> <meta name="citation_author" content="Guan, Min-Xin"> <meta name="citation_author" content="Cang, Xiaohui"> <meta name="citation_doi" content="10.3390/molecules27031071"> <meta name="citation_id" content="mdpi-molecules27031071"> <meta name="citation_abstract_html_url" content="https://www.mdpi.com/1420-3049/27/3/1071"> <meta name="citation_pdf_url" content="https://www.mdpi.com/1420-3049/27/3/1071/pdf?version=1644059024"> <link rel="alternate" type="application/pdf" title="PDF Full-Text" href="https://www.mdpi.com/1420-3049/27/3/1071/pdf?version=1644059024"> <meta name="fulltext_pdf" content="https://www.mdpi.com/1420-3049/27/3/1071/pdf?version=1644059024"> <meta name="citation_fulltext_html_url" content="https://www.mdpi.com/1420-3049/27/3/1071/htm"> <link rel="alternate" type="text/html" title="HTML Full-Text" href="https://www.mdpi.com/1420-3049/27/3/1071/htm"> <meta name="fulltext_html" content="https://www.mdpi.com/1420-3049/27/3/1071/htm"> <link rel="alternate" type="text/xml" title="XML Full-Text" href="https://www.mdpi.com/1420-3049/27/3/1071/xml"> <meta name="fulltext_xml" content="https://www.mdpi.com/1420-3049/27/3/1071/xml"> <meta name="citation_xml_url" content="https://www.mdpi.com/1420-3049/27/3/1071/xml"> <meta name="twitter:card" content="summary" /> <meta name="twitter:site" content="@MDPIOpenAccess" /> <meta name="twitter:image" content="https://pub.mdpi-res.com/img/journals/molecules-logo-social.png?8600e93ff98dbf14" /> <meta property="fb:app_id" content="131189377574"/> <meta property="og:site_name" content="MDPI"/> <meta property="og:type" content="article"/> <meta property="og:url" content="https://www.mdpi.com/1420-3049/27/3/1071" /> <meta property="og:title" content="Investigating the Broad Matrix-Gate Network in the Mitochondrial ADP/ATP Carrier through Molecular Dynamics Simulations" /> <meta property="og:description" content="The mitochondrial ADP/ATP carrier (AAC) exports ATP and imports ADP through alternating between cytosol-open (c-) and matrix-open (m-) states. The salt bridge networks near the matrix side (m-gate) and cytosol side (c-gate) are thought to be crucial for state transitions, yet our knowledge on these networks is still limited. In the current work, we focus on more conserved m-gate network in the c-state AAC. All-atom molecular dynamics (MD) simulations on a variety of mutants and the CATR-AAC complex have revealed that: (1) without involvement of other positive residues, the charged residues from the three Px[DE]xx[KR] motifs only are prone to form symmetrical inter-helical network; (2) R235 plays a determinant role for the asymmetry in m-gate network of AAC; (3) R235 significantly strengthens the interactions between H3 and H5; (4) R79 exhibits more significant impact on m-gate than R279; (5) CATR promotes symmetry in m-gate mainly through separating R234 from D231 and fixing R79; (6) vulnerability of the H2-H3 interface near matrix side could be functionally important. Our results provide new insights into the highly conserved yet variable m-gate network in the big mitochondrial carrier family." /> <meta property="og:image" content="https://pub.mdpi-res.com/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g001-550.jpg?1644059135" /> <link rel="alternate" type="application/rss+xml" title="MDPI Publishing - Latest articles" href="https://www.mdpi.com/rss"> <meta name="google-site-verification" content="PxTlsg7z2S00aHroktQd57fxygEjMiNHydKn3txhvwY"> <meta name="facebook-domain-verification" content="mcoq8dtq6sb2hf7z29j8w515jjoof7" /> <script id="Cookiebot" data-cfasync="false" src="https://consent.cookiebot.com/uc.js" data-cbid="51491ddd-fe7a-4425-ab39-69c78c55829f" type="text/javascript" async></script>  <script type="text/plain" data-cookieconsent="statistics"> (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start': new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0], j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src= 'https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f); })(window,document,'script','dataLayer','GTM-WPK7SW5'); </script> <script type="text/plain" data-cookieconsent="statistics"> _linkedin_partner_id = "2846186"; window._linkedin_data_partner_ids = window._linkedin_data_partner_ids || []; window._linkedin_data_partner_ids.push(_linkedin_partner_id); </script><script type="text/javascript"> (function(){var s = document.getElementsByTagName("script")[0]; var b = document.createElement("script"); b.type = "text/javascript";b.async = true; b.src = "https://snap.licdn.com/li.lms-analytics/insight.min.js"; s.parentNode.insertBefore(b, s);})(); </script> <script type="text/plain" data-cookieconsent="statistics" data-cfasync="false" src="//script.crazyegg.com/pages/scripts/0116/4951.js" async="async" ></script> </head> <body> <div class="direction direction_right" id="small_right" style="border-right-width: 0px; padding:0;"> <i class="fa fa-caret-right fa-2x"></i> </div> <div class="big_direction direction_right" id="big_right" style="border-right-width: 0px;"> <div style="text-align: right;"> Next Article in Journal<br> <div><a href="/1420-3049/27/3/1075">The Pharmaceutical Industry in 2021. An Analysis of FDA Drug Approvals from the Perspective of Molecules</a></div> Next Article in Special Issue<br> <div><a href="/1420-3049/27/4/1420">Interactions between Rhodamine Dyes and Model Membrane Systems—Insights from Molecular Dynamics Simulations</a></div> </div> </div> <div class="direction" id="small_left" style="border-left-width: 0px"> <i class="fa fa-caret-left fa-2x"></i> </div> <div class="big_direction" id="big_left" style="border-left-width: 0px;"> <div> Previous Article in Journal<br> <div><a href="/1420-3049/27/3/1073">Trophic Dynamics and Feeding Ecology of Skipjack Tuna (<i>Katsuwonus pelamis</i>) off Eastern and Western Taiwan</a></div> Previous Article in Special Issue<br> <div><a href="/1420-3049/26/19/6069">Comparing Dimerization Free Energies and Binding Modes of Small Aromatic Molecules with Different Force Fields</a></div> </div> </div> <div style="clear: both;"></div> <div id="menuModal" class="reveal-modal reveal-modal-new reveal-modal-menu" aria-hidden="true" data-reveal role="dialog"> <div class="menu-container"> <div class="UI_NavMenu"> <div class="content__container " > <div class="custom-accordion-for-small-screen-link " > <h2>Journals</h2> </div> <div class="target-item custom-accordion-for-small-screen-content show-for-medium-up"> <div class="menu-container__links"> <div style="width: 100%; float: left;"> <a href="/about/journals">Active Journals</a> <a href="/about/journalfinder">Find a Journal</a> <a href="/about/journals/proposal">Journal Proposal</a> <a href="/about/proceedings">Proceedings Series</a> </div> </div> </div> </div> <a href="/topics"> <h2>Topics</h2> </a> <div class="content__container " > <div class="custom-accordion-for-small-screen-link " > <h2>Information</h2> </div> <div class="target-item custom-accordion-for-small-screen-content show-for-medium-up"> <div class="menu-container__links"> <div style="width: 100%; max-width: 200px; float: left;"> <a href="/authors">For Authors</a> <a href="/reviewers">For Reviewers</a> <a href="/editors">For Editors</a> <a href="/librarians">For Librarians</a> <a href="/publishing_services">For Publishers</a> <a href="/societies">For Societies</a> <a href="/conference_organizers">For Conference Organizers</a> </div> <div style="width: 100%; max-width: 250px; float: left;"> <a href="/openaccess">Open Access Policy</a> <a href="/ioap">Institutional Open Access Program</a> <a href="/special_issues_guidelines">Special Issues Guidelines</a> <a href="/editorial_process">Editorial Process</a> <a href="/ethics">Research and Publication Ethics</a> <a href="/apc">Article Processing Charges</a> <a href="/awards">Awards</a> <a href="/testimonials">Testimonials</a> </div> </div> </div> </div> <a href="/authors/english"> <h2>Author Services</h2> </a> <div class="content__container " > <div class="custom-accordion-for-small-screen-link " > <h2>Initiatives</h2> </div> <div class="target-item custom-accordion-for-small-screen-content show-for-medium-up"> <div class="menu-container__links"> <div style="width: 100%; float: left;"> <a href="https://sciforum.net" target="_blank" rel="noopener noreferrer">Sciforum</a> <a href="https://www.mdpi.com/books" target="_blank" rel="noopener noreferrer">MDPI Books</a> <a href="https://www.preprints.org" target="_blank" rel="noopener noreferrer">Preprints.org</a> <a href="https://www.scilit.com" target="_blank" rel="noopener noreferrer">Scilit</a> <a href="https://sciprofiles.com" target="_blank" rel="noopener noreferrer">SciProfiles</a> <a href="https://encyclopedia.pub" target="_blank" rel="noopener noreferrer">Encyclopedia</a> <a href="https://jams.pub" target="_blank" rel="noopener noreferrer">JAMS</a> <a href="/about/proceedings">Proceedings Series</a> </div> </div> </div> </div> <div class="content__container " > <div class="custom-accordion-for-small-screen-link " > <h2>About</h2> </div> <div class="target-item custom-accordion-for-small-screen-content show-for-medium-up"> <div class="menu-container__links"> <div style="width: 100%; float: left;"> <a href="/about">Overview</a> <a href="/about/contact">Contact</a> <a href="https://careers.mdpi.com" target="_blank" rel="noopener noreferrer">Careers</a> <a href="/about/announcements">News</a> <a href="/about/press">Press</a> <a href="http://blog.mdpi.com/" target="_blank" rel="noopener noreferrer">Blog</a> </div> </div> </div> </div> </div> <div class="menu-container__buttons"> <a class="button UA_SignInUpButton" href="/user/login">Sign In / Sign Up</a> </div> </div> </div> <div id="captchaModal" class="reveal-modal reveal-modal-new reveal-modal-new--small" data-reveal aria-label="Captcha" aria-hidden="true" role="dialog"></div> <div id="actionDisabledModal" class="reveal-modal" data-reveal aria-labelledby="actionDisableModalTitle" aria-hidden="true" role="dialog" style="width: 300px;"> <h2 id="actionDisableModalTitle">Notice</h2> <form action="/email/captcha" method="post" id="emailCaptchaForm"> <div class="row"> <div id="js-action-disabled-modal-text" class="small-12 columns"> </div> <div id="js-action-disabled-modal-submit" class="small-12 columns" style="margin-top: 10px; display: none;"> You can make submissions to other journals <a href="https://susy.mdpi.com/user/manuscripts/upload">here</a>. </div> </div> </form> <a class="close-reveal-modal" aria-label="Close"> <i class="material-icons">clear</i> </a> </div> <div id="rssNotificationModal" class="reveal-modal reveal-modal-new" data-reveal aria-labelledby="rssNotificationModalTitle" aria-hidden="true" role="dialog"> <div class="row"> <div class="small-12 columns"> <h2 id="rssNotificationModalTitle">Notice</h2> <p> You are accessing a machine-readable page. In order to be human-readable, please install an RSS reader. </p> </div> </div> <div class="row"> <div class="small-12 columns"> <a class="button button--color js-rss-notification-confirm">Continue</a> <a class="button button--grey" onclick="$(this).closest('.reveal-modal').find('.close-reveal-modal').click(); return false;">Cancel</a> </div> </div> <a class="close-reveal-modal" aria-label="Close"> <i class="material-icons">clear</i> </a> </div> <div id="drop-article-label-openaccess" class="f-dropdown medium" data-dropdown-content aria-hidden="true" tabindex="-1"> <p> All articles published by MDPI are made immediately available worldwide under an open access license. No special permission is required to reuse all or part of the article published by MDPI, including figures and tables. For articles published under an open access Creative Common CC BY license, any part of the article may be reused without permission provided that the original article is clearly cited. For more information, please refer to <a href="https://www.mdpi.com/openaccess">https://www.mdpi.com/openaccess</a>. </p> </div> <div id="drop-article-label-feature" class="f-dropdown medium" data-dropdown-content aria-hidden="true" tabindex="-1"> <p> Feature papers represent the most advanced research with significant potential for high impact in the field. A Feature Paper should be a substantial original Article that involves several techniques or approaches, provides an outlook for future research directions and describes possible research applications. </p> <p> Feature papers are submitted upon individual invitation or recommendation by the scientific editors and must receive positive feedback from the reviewers. </p> </div> <div id="drop-article-label-choice" class="f-dropdown medium" data-dropdown-content aria-hidden="true" tabindex="-1"> <p> Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal. <div style="margin-top: -10px;"> <div id="drop-article-label-choice-journal-link" style="display: none; margin-top: -10px; padding-top: 10px;"> </div> </div> </p> </div> <div id="drop-article-label-resubmission" class="f-dropdown medium" data-dropdown-content aria-hidden="true" tabindex="-1"> <p> Original Submission Date Received: <span id="drop-article-label-resubmission-date"></span>. </p> </div> <div id="container"> <noscript> <div id="no-javascript"> You seem to have javascript disabled. Please note that many of the page functionalities won't work as expected without javascript enabled. </div> </noscript> <div class="fixed"> <nav class="tab-bar show-for-medium-down"> <div class="row full-width collapse"> <div class="medium-3 small-4 columns"> <a href="/"> <img class="full-size-menu__mdpi-logo" src="https://pub.mdpi-res.com/img/design/mdpi-pub-logo-black-small1.svg?da3a8dcae975a41c?1739526160" style="width: 64px;" title="MDPI Open Access Journals"> </a> </div> <div class="medium-3 small-4 columns right-aligned"> <div class="show-for-medium-down"> <a href="#" style="display: none;"> <i class="material-icons" onclick="$('#menuModal').foundation('reveal', 'close'); return false;">clear</i> </a> <a class="js-toggle-desktop-layout-link" title="Toggle desktop layout" style="display: none;" href="/toggle_desktop_layout_cookie"> <i class="material-icons">zoom_out_map</i> </a> <a href="#" class="js-open-small-search open-small-search"> <i class="material-icons show-for-small only">search</i> </a> <a title="MDPI main page" class="js-open-menu" data-reveal-id="menuModal" href="#"> <i class="material-icons">menu</i> </a> </div> </div> </div> </nav> </div> <section class="main-section"> <header> <div class="full-size-menu show-for-large-up"> <div class="row full-width"> <div class="large-1 columns"> <a href="/"> <img class="full-size-menu__mdpi-logo" src="https://pub.mdpi-res.com/img/design/mdpi-pub-logo-black-small1.svg?da3a8dcae975a41c?1739526160" title="MDPI Open Access Journals"> </a> </div> <div class="large-8 columns text-right UI_NavMenu"> <ul> <li class="menu-item"> <a href="/about/journals" data-dropdown="journals-dropdown" aria-controls="journals-dropdown" aria-expanded="false" data-options="is_hover: true; hover_timeout: 200">Journals</a> <ul id="journals-dropdown" class="f-dropdown dropdown-wrapper dropdown-wrapper__small" data-dropdown-content aria-hidden="true" tabindex="-1"> <li> <div class="row"> <div class="small-12 columns"> <ul> <li> <a href="/about/journals"> Active Journals </a> </li> <li> <a href="/about/journalfinder"> Find a Journal </a> </li> <li> <a href="/about/journals/proposal"> Journal Proposal </a> </li> <li> <a href="/about/proceedings"> Proceedings Series </a> </li> </ul> </div> </div> </li> </ul> </li> <li class="menu-item"> <a href="/topics">Topics</a> </li> <li class="menu-item"> <a href="/authors" data-dropdown="information-dropdown" aria-controls="information-dropdown" aria-expanded="false" data-options="is_hover:true; hover_timeout:200">Information</a> <ul id="information-dropdown" class="f-dropdown dropdown-wrapper" data-dropdown-content aria-hidden="true" tabindex="-1"> <li> <div class="row"> <div class="small-5 columns right-border"> <ul> <li> <a href="/authors">For Authors</a> </li> <li> <a href="/reviewers">For Reviewers</a> </li> <li> <a href="/editors">For Editors</a> </li> <li> <a href="/librarians">For Librarians</a> </li> <li> <a href="/publishing_services">For Publishers</a> </li> <li> <a href="/societies">For Societies</a> </li> <li> <a href="/conference_organizers">For Conference Organizers</a> </li> </ul> </div> <div class="small-7 columns"> <ul> <li> <a href="/openaccess">Open Access Policy</a> </li> <li> <a href="/ioap">Institutional Open Access Program</a> </li> <li> <a href="/special_issues_guidelines">Special Issues Guidelines</a> </li> <li> <a href="/editorial_process">Editorial Process</a> </li> <li> <a href="/ethics">Research and Publication Ethics</a> </li> <li> <a href="/apc">Article Processing Charges</a> </li> <li> <a href="/awards">Awards</a> </li> <li> <a href="/testimonials">Testimonials</a> </li> </ul> </div> </div> </li> </ul> </li> <li class="menu-item"> <a href="/authors/english">Author Services</a> </li> <li class="menu-item"> <a href="/about/initiatives" data-dropdown="initiatives-dropdown" aria-controls="initiatives-dropdown" aria-expanded="false" data-options="is_hover: true; hover_timeout: 200">Initiatives</a> <ul id="initiatives-dropdown" class="f-dropdown dropdown-wrapper dropdown-wrapper__small" data-dropdown-content aria-hidden="true" tabindex="-1"> <li> <div class="row"> <div class="small-12 columns"> <ul> <li> <a href="https://sciforum.net" target="_blank" rel="noopener noreferrer"> Sciforum </a> </li> <li> <a href="https://www.mdpi.com/books" target="_blank" rel="noopener noreferrer"> MDPI Books </a> </li> <li> <a href="https://www.preprints.org" target="_blank" rel="noopener noreferrer"> Preprints.org </a> </li> <li> <a href="https://www.scilit.com" target="_blank" rel="noopener noreferrer"> Scilit </a> </li> <li> <a href="https://sciprofiles.com" target="_blank" rel="noopener noreferrer"> SciProfiles </a> </li> <li> <a href="https://encyclopedia.pub" target="_blank" rel="noopener noreferrer"> Encyclopedia </a> </li> <li> <a href="https://jams.pub" target="_blank" rel="noopener noreferrer"> JAMS </a> </li> <li> <a href="/about/proceedings"> Proceedings Series </a> </li> </ul> </div> </div> </li> </ul> </li> <li class="menu-item"> <a href="/about" data-dropdown="about-dropdown" aria-controls="about-dropdown" aria-expanded="false" data-options="is_hover: true; hover_timeout: 200">About</a> <ul id="about-dropdown" class="f-dropdown dropdown-wrapper dropdown-wrapper__small" data-dropdown-content aria-hidden="true" tabindex="-1"> <li> <div class="row"> <div class="small-12 columns"> <ul> <li> <a href="/about"> Overview </a> </li> <li> <a href="/about/contact"> Contact </a> </li> <li> <a href="https://careers.mdpi.com" target="_blank" rel="noopener noreferrer"> Careers </a> </li> <li> <a href="/about/announcements"> News </a> </li> <li> <a href="/about/press"> Press </a> </li> <li> <a href="http://blog.mdpi.com/" target="_blank" rel="noopener noreferrer"> Blog </a> </li> </ul> </div> </div> </li> </ul> </li> </ul> </div> <div class="large-3 columns text-right full-size-menu__buttons"> <div> <a class="button button--default-inversed UA_SignInUpButton" href="/user/login">Sign In / Sign Up</a> <a class="button button--default js-journal-active-only-link js-journal-active-only-submit-link UC_NavSubmitButton" href=" https://susy.mdpi.com/user/manuscripts/upload?journal=molecules " data-disabledmessage="new submissions are not possible.">Submit</a> </div> </div> </div> </div> <div class="header-divider"> </div> <div class="search-container hide-for-small-down row search-container__homepage-scheme"> <form id="basic_search" style="background-color: inherit !important;" class="large-12 medium-12 columns " action="/search" method="get"> <div class="row search-container__main-elements"> <div class="large-2 medium-2 small-12 columns text-right1 small-only-text-left"> <div class="show-for-medium-up"> <div class="search-input-label"> </div> </div> <span class="search-container__title">Search<span class="hide-for-medium"> for Articles</span><span class="hide-for-small">:</span></span> </div> <div class="custom-accordion-for-small-screen-content"> <div class="large-2 medium-2 small-6 columns "> <div class=""> <div class="search-input-label">Title / Keyword</div> </div> <input type="text" placeholder="Title / Keyword" id="q" tabindex="1" name="q" value="" /> </div> <div class="large-2 medium-2 small-6 columns "> <div class=""> <div class="search-input-label">Author / Affiliation / Email</div> </div> <input type="text" id="authors" placeholder="Author / Affiliation / Email" tabindex="2" name="authors" value="" /> </div> <div class="large-2 medium-2 small-6 columns "> <div class=""> <div class="search-input-label">Journal</div> </div> <select id="journal" tabindex="3" name="journal" class="chosen-select"> <option value="">All Journals</option> <option value="acoustics" > Acoustics </option> <option value="amh" > Acta Microbiologica Hellenica (AMH) </option> <option value="actuators" > Actuators </option> <option value="adhesives" > Adhesives </option> <option value="admsci" > Administrative Sciences </option> <option value="adolescents" > Adolescents </option> <option value="arm" > Advances in Respiratory Medicine (ARM) </option> <option value="aerobiology" > Aerobiology </option> <option value="aerospace" > Aerospace </option> <option value="agriculture" > Agriculture </option> <option value="agriengineering" > AgriEngineering </option> <option value="agrochemicals" > Agrochemicals </option> <option value="agronomy" > Agronomy </option> <option value="ai" > AI </option> <option value="aisens" > AI Sensors </option> <option value="air" > Air </option> <option value="algorithms" > Algorithms </option> <option value="allergies" > Allergies </option> <option value="alloys" > Alloys </option> <option value="analytica" > Analytica </option> <option value="analytics" > Analytics </option> <option value="anatomia" > Anatomia </option> <option value="anesthres" > Anesthesia Research </option> <option value="animals" > Animals </option> <option value="antibiotics" > Antibiotics </option> <option value="antibodies" > Antibodies </option> <option value="antioxidants" > Antioxidants </option> <option value="applbiosci" > Applied Biosciences </option> <option value="applmech" > Applied Mechanics </option> <option value="applmicrobiol" > Applied Microbiology </option> <option value="applnano" > Applied Nano </option> <option value="applsci" > Applied Sciences </option> <option value="asi" > Applied System Innovation (ASI) </option> <option value="appliedchem" > AppliedChem </option> <option value="appliedmath" > AppliedMath </option> <option value="aquacj" > Aquaculture Journal </option> <option value="architecture" > Architecture </option> <option value="arthropoda" > Arthropoda </option> <option value="arts" > Arts </option> <option value="astronomy" > Astronomy </option> <option value="atmosphere" > Atmosphere </option> <option value="atoms" > Atoms </option> <option value="audiolres" > Audiology Research </option> <option value="automation" > Automation </option> <option value="axioms" > Axioms </option> <option value="bacteria" > Bacteria </option> <option value="batteries" > Batteries </option> <option value="behavsci" > Behavioral Sciences </option> <option value="beverages" > Beverages </option> <option value="BDCC" > Big Data and Cognitive Computing (BDCC) </option> <option value="biochem" > BioChem </option> <option value="bioengineering" > Bioengineering </option> <option value="biologics" > Biologics </option> <option value="biology" > Biology </option> <option value="blsf" > Biology and Life Sciences Forum </option> <option value="biomass" > Biomass </option> <option value="biomechanics" > Biomechanics </option> <option value="biomed" > BioMed </option> <option value="biomedicines" > Biomedicines </option> <option value="biomedinformatics" > BioMedInformatics </option> <option value="biomimetics" > Biomimetics </option> <option value="biomolecules" > Biomolecules </option> <option value="biophysica" > Biophysica </option> <option value="biosensors" > Biosensors </option> <option value="biosphere" > Biosphere </option> <option value="biotech" > BioTech </option> <option value="birds" > Birds </option> <option value="blockchains" > Blockchains </option> <option value="brainsci" > Brain Sciences </option> <option value="buildings" > Buildings </option> <option value="businesses" > Businesses </option> <option value="carbon" > C (Journal of Carbon Research) </option> <option value="cancers" > Cancers </option> <option value="cardiogenetics" > Cardiogenetics </option> <option value="catalysts" > Catalysts </option> <option value="cells" > Cells </option> <option value="ceramics" > Ceramics </option> <option value="challenges" > Challenges </option> <option value="ChemEngineering" > ChemEngineering </option> <option value="chemistry" > Chemistry </option> <option value="chemproc" > Chemistry Proceedings </option> <option value="chemosensors" > Chemosensors </option> <option value="children" > Children </option> <option value="chips" > Chips </option> <option value="civileng" > CivilEng </option> <option value="cleantechnol" > Clean Technologies (Clean Technol.) </option> <option value="climate" > Climate </option> <option value="ctn" > Clinical and Translational Neuroscience (CTN) </option> <option value="clinbioenerg" > Clinical Bioenergetics </option> <option value="clinpract" > Clinics and Practice </option> <option value="clockssleep" > Clocks & Sleep </option> <option value="coasts" > Coasts </option> <option value="coatings" > Coatings </option> <option value="colloids" > Colloids and Interfaces </option> <option value="colorants" > Colorants </option> <option value="commodities" > Commodities </option> <option value="complications" > Complications </option> <option value="compounds" > Compounds </option> <option value="computation" > Computation </option> <option value="csmf" > Computer Sciences & Mathematics Forum </option> <option value="computers" > Computers </option> <option value="condensedmatter" > Condensed Matter </option> <option value="conservation" > Conservation </option> <option value="constrmater" > Construction Materials </option> <option value="cmd" > Corrosion and Materials Degradation (CMD) </option> <option value="cosmetics" > Cosmetics </option> <option value="covid" > COVID </option> <option value="cmtr" > Craniomaxillofacial Trauma & Reconstruction (CMTR) </option> <option value="crops" > Crops </option> <option value="cryo" > Cryo </option> <option value="cryptography" > Cryptography </option> <option value="crystals" > Crystals </option> <option value="cimb" > Current Issues in Molecular Biology (CIMB) </option> <option value="curroncol" > Current Oncology </option> <option value="dairy" > Dairy </option> <option value="data" > Data </option> <option value="dentistry" > Dentistry Journal </option> <option value="dermato" > Dermato </option> <option value="dermatopathology" > Dermatopathology </option> <option value="designs" > Designs </option> <option value="diabetology" > Diabetology </option> <option value="diagnostics" > Diagnostics </option> <option value="dietetics" > Dietetics </option> <option value="digital" > Digital </option> <option value="disabilities" > Disabilities </option> <option value="diseases" > Diseases </option> <option value="diversity" > Diversity </option> <option value="dna" > DNA </option> <option value="drones" > Drones </option> <option value="ddc" > Drugs and Drug Candidates (DDC) </option> <option value="dynamics" > Dynamics </option> <option value="earth" > Earth </option> <option value="ecologies" > Ecologies </option> <option value="econometrics" > Econometrics </option> <option value="economies" > Economies </option> <option value="education" > Education Sciences </option> <option value="electricity" > Electricity </option> <option value="electrochem" > Electrochem </option> <option value="electronicmat" > Electronic Materials </option> <option value="electronics" > Electronics </option> <option value="ecm" > Emergency Care and Medicine </option> <option value="encyclopedia" > Encyclopedia </option> <option value="endocrines" > Endocrines </option> <option value="energies" > Energies </option> <option value="esa" > Energy Storage and Applications (ESA) </option> <option value="eng" > Eng </option> <option value="engproc" > Engineering Proceedings </option> <option value="entropy" > Entropy </option> <option value="eesp" > Environmental and Earth Sciences Proceedings </option> <option value="environments" > Environments </option> <option value="epidemiologia" > Epidemiologia </option> <option value="epigenomes" > Epigenomes </option> <option value="ebj" > European Burn Journal (EBJ) </option> <option value="ejihpe" > European Journal of Investigation in Health, Psychology and Education (EJIHPE) </option> <option value="fermentation" > Fermentation </option> <option value="fibers" > Fibers </option> <option value="fintech" > FinTech </option> <option value="fire" > Fire </option> <option value="fishes" > Fishes </option> <option value="fluids" > Fluids </option> <option value="foods" > Foods </option> <option value="forecasting" > Forecasting </option> <option value="forensicsci" > Forensic Sciences </option> <option value="forests" > Forests </option> <option value="fossstud" > Fossil Studies </option> <option value="foundations" > Foundations </option> <option value="fractalfract" > Fractal and Fractional (Fractal Fract) </option> <option value="fuels" > Fuels </option> <option value="future" > Future </option> <option value="futureinternet" > Future Internet </option> <option value="futurepharmacol" > Future Pharmacology </option> <option value="futuretransp" > Future Transportation </option> <option value="galaxies" > Galaxies </option> <option value="games" > Games </option> <option value="gases" > Gases </option> <option value="gastroent" > Gastroenterology Insights </option> <option value="gastrointestdisord" > Gastrointestinal Disorders </option> <option value="gastronomy" > Gastronomy </option> <option value="gels" > Gels </option> <option value="genealogy" > Genealogy </option> <option value="genes" > Genes </option> <option value="geographies" > Geographies </option> <option value="geohazards" > GeoHazards </option> <option value="geomatics" > Geomatics </option> <option value="geometry" > Geometry </option> <option value="geosciences" > Geosciences </option> <option value="geotechnics" > Geotechnics </option> <option value="geriatrics" > Geriatrics </option> <option value="glacies" > Glacies </option> <option value="gucdd" > Gout, Urate, and Crystal Deposition Disease (GUCDD) </option> <option value="grasses" > Grasses </option> <option value="greenhealth" > Green Health </option> <option value="hardware" > Hardware </option> <option value="healthcare" > Healthcare </option> <option value="hearts" > Hearts </option> <option value="hemato" > Hemato </option> <option value="hematolrep" > Hematology Reports </option> <option value="heritage" > Heritage </option> <option value="histories" > Histories </option> <option value="horticulturae" > Horticulturae </option> <option value="hospitals" > Hospitals </option> <option value="humanities" > Humanities </option> <option value="humans" > Humans </option> <option value="hydrobiology" > Hydrobiology </option> <option value="hydrogen" > Hydrogen </option> <option value="hydrology" > Hydrology </option> <option value="hygiene" > Hygiene </option> <option value="immuno" > Immuno </option> <option value="idr" > Infectious Disease Reports </option> <option value="informatics" > Informatics </option> <option value="information" > Information </option> <option value="infrastructures" > Infrastructures </option> <option value="inorganics" > Inorganics </option> <option value="insects" > Insects </option> <option value="instruments" > Instruments </option> <option value="iic" > Intelligent Infrastructure and Construction </option> <option value="ijerph" > International Journal of Environmental Research and Public Health (IJERPH) </option> <option value="ijfs" > International Journal of Financial Studies (IJFS) </option> <option value="ijms" > International Journal of Molecular Sciences (IJMS) </option> <option value="IJNS" > International Journal of Neonatal Screening (IJNS) </option> <option value="ijom" > International Journal of Orofacial Myology and Myofunctional Therapy (IJOM) </option> <option value="ijpb" > International Journal of Plant Biology (IJPB) </option> <option value="ijt" > International Journal of Topology </option> <option value="ijtm" > International Journal of Translational Medicine (IJTM) </option> <option value="ijtpp" > International Journal of Turbomachinery, Propulsion and Power (IJTPP) </option> <option value="ime" > International Medical Education (IME) </option> <option value="inventions" > Inventions </option> <option value="IoT" > IoT </option> <option value="ijgi" > ISPRS International Journal of Geo-Information (IJGI) </option> <option value="J" > J </option> <option value="jal" > Journal of Ageing and Longevity (JAL) </option> <option value="jcdd" > Journal of Cardiovascular Development and Disease (JCDD) </option> <option value="jcto" > Journal of Clinical & Translational Ophthalmology (JCTO) </option> <option value="jcm" > Journal of Clinical Medicine (JCM) </option> <option value="jcs" > Journal of Composites Science (J. Compos. Sci.) </option> <option value="jcp" > Journal of Cybersecurity and Privacy (JCP) </option> <option value="jdad" > Journal of Dementia and Alzheimer's Disease (JDAD) </option> <option value="jdb" > Journal of Developmental Biology (JDB) </option> <option value="jeta" > Journal of Experimental and Theoretical Analyses (JETA) </option> <option value="jemr" > Journal of Eye Movement Research (JEMR) </option> <option value="jfb" > Journal of Functional Biomaterials (JFB) </option> <option value="jfmk" > Journal of Functional Morphology and Kinesiology (JFMK) </option> <option value="jof" > Journal of Fungi (JoF) </option> <option value="jimaging" > Journal of Imaging (J. Imaging) </option> <option value="jintelligence" > Journal of Intelligence (J. Intell.) </option> <option value="jlpea" > Journal of Low Power Electronics and Applications (JLPEA) </option> <option value="jmmp" > Journal of Manufacturing and Materials Processing (JMMP) </option> <option value="jmse" > Journal of Marine Science and Engineering (JMSE) </option> <option value="jmahp" > Journal of Market Access & Health Policy (JMAHP) </option> <option value="jmms" > Journal of Mind and Medical Sciences (JMMS) </option> <option value="jmp" > Journal of Molecular Pathology (JMP) </option> <option value="jnt" > Journal of Nanotheranostics (JNT) </option> <option value="jne" > Journal of Nuclear Engineering (JNE) </option> <option value="ohbm" > Journal of Otorhinolaryngology, Hearing and Balance Medicine (JOHBM) </option> <option value="jop" > Journal of Parks </option> <option value="jpm" > Journal of Personalized Medicine (JPM) </option> <option value="jpbi" > Journal of Pharmaceutical and BioTech Industry (JPBI) </option> <option value="jor" > Journal of Respiration (JoR) </option> <option value="jrfm" > Journal of Risk and Financial Management (JRFM) </option> <option value="jsan" > Journal of Sensor and Actuator Networks (JSAN) </option> <option value="joma" > Journal of the Oman Medical Association (JOMA) </option> <option value="jtaer" > Journal of Theoretical and Applied Electronic Commerce Research (JTAER) </option> <option value="jvd" > Journal of Vascular Diseases (JVD) </option> <option value="jox" > Journal of Xenobiotics (JoX) </option> <option value="jzbg" > Journal of Zoological and Botanical Gardens (JZBG) </option> <option value="journalmedia" > Journalism and Media </option> <option value="kidneydial" > Kidney and Dialysis </option> <option value="kinasesphosphatases" > Kinases and Phosphatases </option> <option value="knowledge" > Knowledge </option> <option value="labmed" > LabMed </option> <option value="laboratories" > Laboratories </option> <option value="land" > Land </option> <option value="languages" > Languages </option> <option value="laws" > Laws </option> <option value="life" > Life </option> <option value="limnolrev" > Limnological Review </option> <option value="lipidology" > Lipidology </option> <option value="liquids" > Liquids </option> <option value="literature" > Literature </option> <option value="livers" > Livers </option> <option value="logics" > Logics </option> <option value="logistics" > Logistics </option> <option value="lubricants" > Lubricants </option> <option value="lymphatics" > Lymphatics </option> <option value="make" > Machine Learning and Knowledge Extraction (MAKE) </option> <option value="machines" > Machines </option> <option value="macromol" > Macromol </option> <option value="magnetism" > Magnetism </option> <option value="magnetochemistry" > Magnetochemistry </option> <option value="marinedrugs" > Marine Drugs </option> <option value="materials" > Materials </option> <option value="materproc" > Materials Proceedings </option> <option value="mca" > Mathematical and Computational Applications (MCA) </option> <option value="mathematics" > Mathematics </option> <option value="medsci" > Medical Sciences </option> <option value="msf" > Medical Sciences Forum </option> <option value="medicina" > Medicina </option> <option value="medicines" > Medicines </option> <option value="membranes" > Membranes </option> <option value="merits" > Merits </option> <option value="metabolites" > Metabolites </option> <option value="metals" > Metals </option> <option value="meteorology" > Meteorology </option> <option value="methane" > Methane </option> <option value="mps" > Methods and Protocols (MPs) </option> <option value="metrics" > Metrics </option> <option value="metrology" > Metrology </option> <option value="micro" > Micro </option> <option value="microbiolres" > Microbiology Research </option> <option value="micromachines" > Micromachines </option> <option value="microorganisms" > Microorganisms </option> <option value="microplastics" > Microplastics </option> <option value="microwave" > Microwave </option> <option value="minerals" > Minerals </option> <option value="mining" > Mining </option> <option value="modelling" > Modelling </option> <option value="mmphys" > Modern Mathematical Physics </option> <option value="molbank" > Molbank </option> <option value="molecules" selected='selected'> Molecules </option> <option value="mti" > Multimodal Technologies and Interaction (MTI) </option> <option value="muscles" > Muscles </option> <option value="nanoenergyadv" > Nanoenergy Advances </option> <option value="nanomanufacturing" > Nanomanufacturing </option> <option value="nanomaterials" > Nanomaterials </option> <option value="ndt" > NDT </option> <option value="network" > Network </option> <option value="neuroglia" > Neuroglia </option> <option value="neurolint" > Neurology International </option> <option value="neurosci" > NeuroSci </option> <option value="nitrogen" > Nitrogen </option> <option value="ncrna" > Non-Coding RNA (ncRNA) </option> <option value="nursrep" > Nursing Reports </option> <option value="nutraceuticals" > Nutraceuticals </option> <option value="nutrients" > Nutrients </option> <option value="obesities" > Obesities </option> <option value="oceans" > Oceans </option> <option value="onco" > Onco </option> <option value="optics" > Optics </option> <option value="oral" > Oral </option> <option value="organics" > Organics </option> <option value="organoids" > Organoids </option> <option value="osteology" > Osteology </option> <option value="oxygen" > Oxygen </option> <option value="parasitologia" > Parasitologia </option> <option value="particles" > Particles </option> <option value="pathogens" > Pathogens </option> <option value="pathophysiology" > Pathophysiology </option> <option value="pediatrrep" > Pediatric Reports </option> <option value="pets" > Pets </option> <option value="pharmaceuticals" > Pharmaceuticals </option> <option value="pharmaceutics" > Pharmaceutics </option> <option value="pharmacoepidemiology" > Pharmacoepidemiology </option> <option value="pharmacy" > Pharmacy </option> <option value="philosophies" > Philosophies </option> <option value="photochem" > Photochem </option> <option value="photonics" > Photonics </option> <option value="phycology" > Phycology </option> <option value="physchem" > Physchem </option> <option value="psf" > Physical Sciences Forum </option> <option value="physics" > Physics </option> <option value="physiologia" > Physiologia </option> <option value="plants" > Plants </option> <option value="plasma" > Plasma </option> <option value="platforms" > Platforms </option> <option value="pollutants" > Pollutants </option> <option value="polymers" > Polymers </option> <option value="polysaccharides" > Polysaccharides </option> <option value="populations" > Populations </option> <option value="poultry" > Poultry </option> <option value="powders" > Powders </option> <option value="proceedings" > Proceedings </option> <option value="processes" > Processes </option> <option value="prosthesis" > Prosthesis </option> <option value="proteomes" > Proteomes </option> <option value="psychiatryint" > Psychiatry International </option> <option value="psychoactives" > Psychoactives </option> <option value="psycholint" > Psychology International </option> <option value="publications" > Publications </option> <option value="qubs" > Quantum Beam Science (QuBS) </option> <option value="quantumrep" > Quantum Reports </option> <option value="quaternary" > Quaternary </option> <option value="radiation" > Radiation </option> <option value="reactions" > Reactions </option> <option value="realestate" > Real Estate </option> <option value="receptors" > Receptors </option> <option value="recycling" > Recycling </option> <option value="rsee" > Regional Science and Environmental Economics (RSEE) </option> <option value="religions" > Religions </option> <option value="remotesensing" > Remote Sensing </option> <option value="reports" > Reports </option> <option value="reprodmed" > Reproductive Medicine (Reprod. Med.) </option> <option value="resources" > Resources </option> <option value="rheumato" > Rheumato </option> <option value="risks" > Risks </option> <option value="robotics" > Robotics </option> <option value="ruminants" > Ruminants </option> <option value="safety" > Safety </option> <option value="sci" > Sci </option> <option value="scipharm" > Scientia Pharmaceutica (Sci. Pharm.) </option> <option value="sclerosis" > Sclerosis </option> <option value="seeds" > Seeds </option> <option value="sensors" > Sensors </option> <option value="separations" > Separations </option> <option value="sexes" > Sexes </option> <option value="signals" > Signals </option> <option value="sinusitis" > Sinusitis </option> <option value="smartcities" > Smart Cities </option> <option value="socsci" > Social Sciences </option> <option value="siuj" > Société Internationale d’Urologie Journal (SIUJ) </option> <option value="societies" > Societies </option> <option value="software" > Software </option> <option value="soilsystems" > Soil Systems </option> <option value="solar" > Solar </option> <option value="solids" > Solids </option> <option value="spectroscj" > Spectroscopy Journal </option> <option value="sports" > Sports </option> <option value="standards" > Standards </option> <option value="stats" > Stats </option> <option value="stresses" > Stresses </option> <option value="surfaces" > Surfaces </option> <option value="surgeries" > Surgeries </option> <option value="std" > Surgical Techniques Development </option> <option value="sustainability" > Sustainability </option> <option value="suschem" > Sustainable Chemistry </option> <option value="symmetry" > Symmetry </option> <option value="synbio" > SynBio </option> <option value="systems" > Systems </option> <option value="targets" > Targets </option> <option value="taxonomy" > Taxonomy </option> <option value="technologies" > Technologies </option> <option value="telecom" > Telecom </option> <option value="textiles" > Textiles </option> <option value="thalassrep" > Thalassemia Reports </option> <option value="therapeutics" > Therapeutics </option> <option value="thermo" > Thermo </option> <option value="timespace" > Time and Space </option> <option value="tomography" > Tomography </option> <option value="tourismhosp" > Tourism and Hospitality </option> <option value="toxics" > Toxics </option> <option value="toxins" > Toxins </option> <option value="transplantology" > Transplantology </option> <option value="traumacare" > Trauma Care </option> <option value="higheredu" > Trends in Higher Education </option> <option value="tropicalmed" > Tropical Medicine and Infectious Disease (TropicalMed) </option> <option value="universe" > Universe </option> <option value="urbansci" > Urban Science </option> <option value="uro" > Uro </option> <option value="vaccines" > Vaccines </option> <option value="vehicles" > Vehicles </option> <option value="venereology" > Venereology </option> <option value="vetsci" > Veterinary Sciences </option> <option value="vibration" > Vibration </option> <option value="virtualworlds" > Virtual Worlds </option> <option value="viruses" > Viruses </option> <option value="vision" > Vision </option> <option value="waste" > Waste </option> <option value="water" > Water </option> <option value="wild" > Wild </option> <option value="wind" > Wind </option> <option value="women" > Women </option> <option value="world" > World </option> <option value="wevj" > World Electric Vehicle Journal (WEVJ) </option> <option value="youth" > Youth </option> <option value="zoonoticdis" > Zoonotic Diseases </option> </select> </div> <div class="large-2 medium-2 small-6 columns "> <div class=""> <div class="search-input-label">Article Type</div> </div> <select id="article_type" tabindex="4" name="article_type" class="chosen-select"> <option value="">All Article Types</option> <option value="research-article">Article</option> <option value="review-article">Review</option> <option value="rapid-communication">Communication</option> <option value="editorial">Editorial</option> <option value="abstract">Abstract</option> <option value="book-review">Book Review</option> <option value="brief-communication">Brief Communication</option> <option value="brief-report">Brief Report</option> <option value="case-report">Case Report</option> <option value="clinicopathological-challenge">Clinicopathological Challenge</option> <option value="article-commentary">Comment</option> <option value="commentary">Commentary</option> <option value="concept-paper">Concept Paper</option> <option value="conference-report">Conference Report</option> <option value="correction">Correction</option> <option value="creative">Creative</option> <option value="data-descriptor">Data Descriptor</option> <option value="discussion">Discussion</option> <option value="Entry">Entry</option> <option value="essay">Essay</option> <option value="expression-of-concern">Expression of Concern</option> <option value="extended-abstract">Extended Abstract</option> <option value="field-guide">Field Guide</option> <option value="giants-in-urology">Giants in Urology</option> <option value="guidelines">Guidelines</option> <option value="hypothesis">Hypothesis</option> <option value="interesting-image">Interesting Images</option> <option value="letter">Letter</option> <option value="books-received">New Book Received</option> <option value="obituary">Obituary</option> <option value="opinion">Opinion</option> <option value="perspective">Perspective</option> <option value="proceedings">Proceeding Paper</option> <option value="project-report">Project Report</option> <option value="protocol">Protocol</option> <option value="registered-report">Registered Report</option> <option value="reply">Reply</option> <option value="retraction">Retraction</option> <option value="note">Short Note</option> <option value="study-protocol">Study Protocol</option> <option value="systematic_review">Systematic Review</option> <option value="technical-note">Technical Note</option> <option value="tutorial">Tutorial</option> <option value="urology-around-the-world">Urology around the World</option> <option value="viewpoint">Viewpoint</option> </select> </div> <div class="large-1 medium-1 small-6 end columns small-push-6 medium-reset-order large-reset-order js-search-collapsed-button-container"> <div class="search-input-label"> </div> <input type="submit" id="search" value="Search" class="button button--dark button--full-width searchButton1 US_SearchButton" tabindex="12"> </div> <div class="large-1 medium-1 small-6 end columns large-text-left small-only-text-center small-pull-6 medium-reset-order large-reset-order js-search-collapsed-link-container"> <div class="search-input-label"> </div> <a class="main-search-clear search-container__link" href="#" onclick="openAdvanced(''); return false;">Advanced<span class="show-for-small-only"> Search</span></a> </div> </div> </div> <div class="search-container__advanced" style="margin-top: 0; padding-top: 0px; background-color: inherit; color: inherit;"> <div class="row"> <div class="large-2 medium-2 columns show-for-medium-up"> </div> <div class="large-2 medium-2 small-6 columns "> <div class=""> <div class="search-input-label">Section</div> </div> <select id="section" tabindex="5" name="section" class="chosen-select"> <option value=""></option> </select> </div> <div class="large-2 medium-2 small-6 columns "> <div class=""> <div class="search-input-label">Special Issue</div> </div> <select id="special_issue" tabindex="6" name="special_issue" class="chosen-select"> <option value=""></option> </select> </div> <div class="large-1 medium-1 small-6 end columns "> <div class="search-input-label">Volume</div> <input type="text" id="volume" tabindex="7" name="volume" placeholder="..." value="27" /> </div> <div class="large-1 medium-1 small-6 end columns "> <div class="search-input-label">Issue</div> <input type="text" id="issue" tabindex="8" name="issue" placeholder="..." value="3" /> </div> <div class="large-1 medium-1 small-6 end columns "> <div class="search-input-label">Number</div> <input type="text" id="number" tabindex="9" name="number" placeholder="..." value="" /> </div> <div class="large-1 medium-1 small-6 end columns "> <div class="search-input-label">Page</div> <input type="text" id="page" tabindex="10" name="page" placeholder="..." value="" /> </div> <div class="large-1 medium-1 small-6 columns small-push-6 medium-reset order large-reset-order medium-reset-order js-search-expanded-button-container"></div> <div class="large-1 medium-1 small-6 columns large-text-left small-only-text-center small-pull-6 medium-reset-order large-reset-order js-search-expanded-link-container"></div> </div> </div> </form> <form id="advanced-search" class="large-12 medium-12 columns"> <div class="search-container__advanced"> <div id="advanced-search-template" class="row advanced-search-row"> <div class="large-2 medium-2 small-12 columns show-for-medium-up"> </div> <div class="large-2 medium-2 small-3 columns connector-div"> <div class="search-input-label"><span class="show-for-medium-up">Logical Operator</span><span class="show-for-small">Operator</span></div> <select class="connector"> <option value="and">AND</option> <option value="or">OR</option> </select> </div> <div class="large-3 medium-3 small-6 columns search-text-div"> <div class="search-input-label">Search Text</div> <input type="text" class="search-text" placeholder="Search text"> </div> <div class="large-2 medium-2 small-6 large-offset-0 medium-offset-0 small-offset-3 columns search-field-div"> <div class="search-input-label">Search Type</div> <select class="search-field"> <option value="all">All fields</option> <option value="title">Title</option> <option value="abstract">Abstract</option> <option value="keywords">Keywords</option> <option value="authors">Authors</option> <option value="affiliations">Affiliations</option> <option value="doi">Doi</option> <option value="full_text">Full Text</option> <option value="references">References</option> </select> </div> <div class="large-1 medium-1 small-3 columns"> <div class="search-input-label"> </div> <div class="search-action-div"> <div class="search-plus"> <i class="material-icons">add_circle_outline</i> </div> </div> <div class="search-action-div"> <div class="search-minus"> <i class="material-icons">remove_circle_outline</i> </div> </div> </div> <div class="large-1 medium-1 small-6 large-offset-0 medium-offset-0 small-offset-3 end columns"> <div class="search-input-label"> </div> <input class="advanced-search-button button button--dark search-submit" type="submit" value="Search"> </div> <div class="large-1 medium-1 small-6 end columns show-for-medium-up"></div> </div> </div> </form> </div> <div class="header-divider"> </div> <div class="breadcrumb row full-row"> <div class="breadcrumb__element"> <a href="/about/journals">Journals</a> </div> <div class="breadcrumb__element"> <a href="/journal/molecules">Molecules</a> </div> <div class="breadcrumb__element"> <a href="/1420-3049/27">Volume 27</a> </div> <div class="breadcrumb__element"> <a href="/1420-3049/27/3">Issue 3</a> </div> <div class="breadcrumb__element"> <a href="#">10.3390/molecules27031071</a> </div> </div> </header> <div id="main-content" class=""> <div class="row full-width row-fixed-left-column"> <div id="left-column" class="content__column large-3 medium-3 small-12 columns"> <div class="content__container"> <a href="/journal/molecules"> <img src="https://pub.mdpi-res.com/img/journals/molecules-logo.png?8600e93ff98dbf14" alt="molecules-logo" title="Molecules" style="max-height: 60px; margin: 0 0 0 0;"> </a> <div class="generic-item no-border"> <a class="button button--color button--full-width js-journal-active-only-link js-journal-active-only-submit-link UC_ArticleSubmitButton" href="https://susy.mdpi.com/user/manuscripts/upload?form%5Bjournal_id%5D%3D1" data-disabledmessage="creating new submissions is not possible."> Submit to this Journal </a> <a class="button button--color button--full-width js-journal-active-only-link UC_ArticleReviewButton" href="https://susy.mdpi.com/volunteer/journals/review" data-disabledmessage="volunteering as journal reviewer is not possible."> Review for this Journal </a> <a class="button button--color-inversed button--color-journal button--full-width js-journal-active-only-link UC_ArticleEditIssueButton" href="/journalproposal/sendproposalspecialissue/molecules" data-path="/1420-3049/27/3/1071" data-disabledmessage="proposing new special issue is not possible."> Propose a Special Issue </a> </div> <div class="generic-item link-article-menu show-for-small"> <a href="#" class="link-article-menu show-for-small"> <span class="closed">►</span> <span class="open" style="display: none;">▼</span> Article Menu </a> </div> <div class="hide-small-down-initially UI_ArticleMenu"> <div class="generic-item"> <h2>Article Menu</h2> </div> <ul class="accordion accordion__menu" data-accordion data-options="multi_expand:true;toggleable: true"> <li class="accordion-navigation"> <a href="#academic_editors" class="accordion__title">Academic Editors</a> <div id="academic_editors" class="content active"> <div class="academic-editor-container " title=""> <div class="sciprofiles-link" style="display: inline-block"> <div class="sciprofiles-link__link"> <img class="sciprofiles-link__image" src="https://pub.mdpi-res.com/bundles/mdpisciprofileslink/img/unknown-user.png?1739526160" style="width: auto; height: 16px; border-radius: 50%;"> <span class="sciprofiles-link__name" style="line-height: 36px;">Luís M. S. Loura</span> </div> </div> </div> <div class="academic-editor-container " title=""> <div class="sciprofiles-link" style="display: inline-block"> <div class="sciprofiles-link__link"> <img class="sciprofiles-link__image" src="https://pub.mdpi-res.com/bundles/mdpisciprofileslink/img/unknown-user.png?1739526160" style="width: auto; height: 16px; border-radius: 50%;"> <span class="sciprofiles-link__name" style="line-height: 36px;">Hugo A. L. Filipe</span> </div> </div> </div> </div> </li> <li class="accordion-direct-link"> <a href="/1420-3049/27/3/1071/scifeed_display" data-reveal-id="scifeed-modal" data-reveal-ajax="true">Subscribe SciFeed</a> </li> <li class="accordion-direct-link js-article-similarity-container" style="display: none"> <a href="#" class="js-similarity-related-articles">Recommended Articles</a> </li> <li class="accordion-navigation"> <a href="#related" class="accordion__title">Related Info Links</a> <div id="related" class="content UI_ArticleMenu_RelatedLinks"> <ul> <li class="li-link"> <a href="http://www.ncbi.nlm.nih.gov/sites/entrez/35164338" target="_blank" rel="noopener noreferrer">PubMed/Medline</a> </li> <li class="li-link"> <a href="https://scholar.google.com/scholar?q=Investigating%20the%20Broad%20Matrix-Gate%20Network%20in%20the%20Mitochondrial%20ADP%2FATP%20Carrier%20through%20Molecular%20Dynamics%20Simulations" target="_blank" rel="noopener noreferrer">Google Scholar</a> </li> </ul> </div> </li> <li class="accordion-navigation"> <a href="#authors" class="accordion__title">More by Authors Links</a> <div id="authors" class="content UI_ArticleMenu_AuthorsLinks"> <ul class="side-menu-ul"> <li> <a class="expand" onclick='$(this).closest("li").next("div").toggle(); return false;'>on DOAJ</a> </li> <div id="AuthorDOAJExpand" style="display:none;"> <ul class="submenu"> <li class="li-link"> <a href='http://doaj.org/search/articles?source=%7B%22query%22%3A%7B%22query_string%22%3A%7B%22query%22%3A%22%5C%22Shihao%20Yao%5C%22%22%2C%22default_operator%22%3A%22AND%22%2C%22default_field%22%3A%22bibjson.author.name%22%7D%7D%7D' target="_blank" rel="noopener noreferrer">Yao, S.</a> <li> </li> <li class="li-link"> <a href='http://doaj.org/search/articles?source=%7B%22query%22%3A%7B%22query_string%22%3A%7B%22query%22%3A%22%5C%22Boyuan%20Ma%5C%22%22%2C%22default_operator%22%3A%22AND%22%2C%22default_field%22%3A%22bibjson.author.name%22%7D%7D%7D' target="_blank" rel="noopener noreferrer">Ma, B.</a> <li> </li> <li class="li-link"> <a href='http://doaj.org/search/articles?source=%7B%22query%22%3A%7B%22query_string%22%3A%7B%22query%22%3A%22%5C%22Qiuzi%20Yi%5C%22%22%2C%22default_operator%22%3A%22AND%22%2C%22default_field%22%3A%22bibjson.author.name%22%7D%7D%7D' target="_blank" rel="noopener noreferrer">Yi, Q.</a> <li> </li> <li class="li-link"> <a href='http://doaj.org/search/articles?source=%7B%22query%22%3A%7B%22query_string%22%3A%7B%22query%22%3A%22%5C%22Min-Xin%20Guan%5C%22%22%2C%22default_operator%22%3A%22AND%22%2C%22default_field%22%3A%22bibjson.author.name%22%7D%7D%7D' target="_blank" rel="noopener noreferrer">Guan, M.</a> <li> </li> <li class="li-link"> <a href='http://doaj.org/search/articles?source=%7B%22query%22%3A%7B%22query_string%22%3A%7B%22query%22%3A%22%5C%22Xiaohui%20Cang%5C%22%22%2C%22default_operator%22%3A%22AND%22%2C%22default_field%22%3A%22bibjson.author.name%22%7D%7D%7D' target="_blank" rel="noopener noreferrer">Cang, X.</a> <li> </li> </ul> </div> <li> <a class="expand" onclick='$(this).closest("li").next("div").toggle(); return false;'>on Google Scholar</a> </li> <div id="AuthorGoogleExpand" style="display:none;"> <ul class="submenu"> <li class="li-link"> <a href="https://scholar.google.com/scholar?q=Shihao%20Yao" target="_blank" rel="noopener noreferrer">Yao, S.</a> <li> </li> <li class="li-link"> <a href="https://scholar.google.com/scholar?q=Boyuan%20Ma" target="_blank" rel="noopener noreferrer">Ma, B.</a> <li> </li> <li class="li-link"> <a href="https://scholar.google.com/scholar?q=Qiuzi%20Yi" target="_blank" rel="noopener noreferrer">Yi, Q.</a> <li> </li> <li class="li-link"> <a href="https://scholar.google.com/scholar?q=Min-Xin%20Guan" target="_blank" rel="noopener noreferrer">Guan, M.</a> <li> </li> <li class="li-link"> <a href="https://scholar.google.com/scholar?q=Xiaohui%20Cang" target="_blank" rel="noopener noreferrer">Cang, X.</a> <li> </li> </ul> </div> <li> <a class="expand" onclick='$(this).closest("li").next("div").toggle(); return false;'>on PubMed</a> </li> <div id="AuthorPubMedExpand" style="display:none;"> <ul class="submenu"> <li class="li-link"> <a href="http://www.pubmed.gov/?cmd=Search&term=Shihao%20Yao" target="_blank" rel="noopener noreferrer">Yao, S.</a> <li> </li> <li class="li-link"> <a href="http://www.pubmed.gov/?cmd=Search&term=Boyuan%20Ma" target="_blank" rel="noopener noreferrer">Ma, B.</a> <li> </li> <li class="li-link"> <a href="http://www.pubmed.gov/?cmd=Search&term=Qiuzi%20Yi" target="_blank" rel="noopener noreferrer">Yi, Q.</a> <li> </li> <li class="li-link"> <a href="http://www.pubmed.gov/?cmd=Search&term=Min-Xin%20Guan" target="_blank" rel="noopener noreferrer">Guan, M.</a> <li> </li> <li class="li-link"> <a href="http://www.pubmed.gov/?cmd=Search&term=Xiaohui%20Cang" target="_blank" rel="noopener noreferrer">Cang, X.</a> <li> </li> </ul> </div> </ul> </div> </li> </ul> <span style="display:none" id="scifeed_hidden_flag"></span> <span style="display:none" id="scifeed_subscribe_url">/ajax/scifeed/subscribe</span> </div> </div> <div class="content__container responsive-moving-container large medium active hidden" data-id="article-counters"> <div id="counts-wrapper" class="row generic-item no-border" data-equalizer> <div id="js-counts-wrapper__views" class="small-12 hide columns count-div-container"> <a href="#metrics" > <div class="count-div" data-equalizer-watch> <span class="name">Article Views</span> <span class="count view-number"></span> </div> </a> </div> <div id="js-counts-wrapper__citations" class="small-12 columns hide count-div-container"> <a href="#metrics" > <div class="count-div" data-equalizer-watch> <span class="name">Citations</span> <span class="count citations-number Var_ArticleMaxCitations">-</span> </div> </a> </div> </div> </div> <div class="content__container"> <div class="hide-small-down-initially"> <ul class="accordion accordion__menu" data-accordion data-options="multi_expand:true;toggleable: true"> <li class="accordion-navigation"> <a href="#table_of_contents" class="accordion__title">Table of Contents</a> <div id="table_of_contents" class="content active"> <div class="menu-caption" id="html-quick-links-title"></div> </div> </li> </ul> </div> </div>  <div id="pbgrd-sky"></div> <script src="https://cdn.pbgrd.com/core-mdpi.js"></script> <style>.content__container { min-width: 300px; }</style>  </div> <div id="middle-column" class="content__column large-9 medium-9 small-12 columns end middle-bordered"> <div class="middle-column__help"> <div class="middle-column__help__fixed show-for-medium-up"> <span id="js-altmetrics-donut" href="#" target="_blank" rel="noopener noreferrer" style="display: none;"> <span data-badge-type='donut' class='altmetric-embed' data-doi='10.3390/molecules27031071'></span> <span>Altmetric</span> </span> <a href="#" class="UA_ShareButton" data-reveal-id="main-share-modal" title="Share"> <i class="material-icons">share</i> <span>Share</span> </a> <a href="#" data-reveal-id="main-help-modal" title="Help"> <i class="material-icons">announcement</i> <span>Help</span> </a> <a href="javascript:void(0);" data-reveal-id="cite-modal" data-counterslink = "https://www.mdpi.com/1420-3049/27/3/1071/cite" > <i class="material-icons">format_quote</i> <span>Cite</span> </a> <a href="https://sciprofiles.com/discussion-groups/public/10.3390/molecules27031071?utm_source=mpdi.com&utm_medium=publication&utm_campaign=discuss_in_sciprofiles" target="_blank" rel="noopener noreferrer" title="Discuss in Sciprofiles"> <i class="material-icons">question_answer</i> <span>Discuss in SciProfiles</span> </a> </div> <div id="main-help-modal" class="reveal-modal reveal-modal-new" data-reveal aria-labelledby="modalTitle" aria-hidden="true" role="dialog"> <div class="row"> <div class="small-12 columns"> <h2 style="margin: 0;">Need Help?</h2> </div> <div class="small-6 columns"> <h3>Support</h3> <p> Find support for a specific problem in the support section of our website. </p> <a target="_blank" href="/about/contactform" class="button button--color button--full-width"> Get Support </a> </div> <div class="small-6 columns"> <h3>Feedback</h3> <p> Please let us know what you think of our products and services. </p> <a target="_blank" href="/feedback/send" class="button button--color button--full-width"> Give Feedback </a> </div> <div class="small-6 columns end"> <h3>Information</h3> <p> Visit our dedicated information section to learn more about MDPI. </p> <a target="_blank" href="/authors" class="button button--color button--full-width"> Get Information </a> </div> </div> <a class="close-reveal-modal" aria-label="Close"> <i class="material-icons">clear</i> </a> </div> </div> <div class="middle-column__main "> <div class="page-highlight"> <style type="text/css"> img.review-status { width: 30px; } </style> <div id="jmolModal" class="reveal-modal" data-reveal aria-labelledby="Captcha" aria-hidden="true" role="dialog"> <h2>JSmol Viewer</h2> <div class="row"> <div class="small-12 columns text-center"> <iframe style="width: 520px; height: 520px;" frameborder="0" id="jsmol-content"></iframe> <div class="content"></div> </div> </div> <a class="close-reveal-modal" aria-label="Close"> <i class="material-icons">clear</i> </a> </div> <div itemscope itemtype="http://schema.org/ScholarlyArticle" id="abstract" class="abstract_div"> <div class="js-check-update-container"></div> <div class="html-content__container content__container content__container__combined-for-large__first" style="overflow: auto; position: inherit;"> <div class='html-profile-nav'> <div class='top-bar'> <div class='nav-sidebar-btn show-for-large-up' data-status='opened' > <i class='material-icons'>first_page</i> </div> <a id="js-button-download" class="button button--color-inversed" style="display: none;" href="/1420-3049/27/3/1071/pdf?version=1644059024" data-name="Investigating the Broad Matrix-Gate Network in the Mitochondrial ADP/ATP Carrier through Molecular Dynamics Simulations" data-journal="molecules"> <i class="material-icons custom-download"></i> Download PDF </a> <div class='nav-btn'> <i class='material-icons'>settings</i> </div> <a href="/1420-3049/27/3/1071/reprints" id="js-button-reprints" class="button button--color-inversed"> Order Article Reprints </a> </div> <div class='html-article-menu'> <div class='html-first-step row'> <div class='html-font-family large-6 medium-6 small-12 columns'> <div class='row'> <div class='html-font-label large-4 medium-4 small-12 columns'> Font Type: </div> <div class='large-8 medium-8 small-12 columns'> <span class="html-article-menu-option"><i style='font-family:Arial, Arial, Helvetica, sans-serif;' data-fontfamily='Arial, Arial, Helvetica, sans-serif'>Arial</i></span> <span class="html-article-menu-option"><i style='font-family:Georgia1, Georgia, serif;' data-fontfamily='Georgia1, Georgia, serif'>Georgia</i></span> <span class="html-article-menu-option"><i style='font-family:Verdana, Verdana, Geneva, sans-serif;' data-fontfamily='Verdana, Verdana, Geneva, sans-serif' >Verdana</i></span> </div> </div> </div> <div class='html-font-resize large-6 medium-6 small-12 columns'> <div class='row'> <div class='html-font-label large-4 medium-4 small-12 columns'>Font Size:</div> <div class='large-8 medium-8 small-12 columns'> <span class="html-article-menu-option a1" data-percent="100">Aa</span> <span class="html-article-menu-option a2" data-percent="120">Aa</span> <span class="html-article-menu-option a3" data-percent="160">Aa</span> </div> </div> </div> </div> <div class='row'> <div class='html-line-space large-6 medium-6 small-12 columns'> <div class='row'> <div class='html-font-label large-4 medium-4 small-12 columns' >Line Spacing:</div> <div class='large-8 medium-8 small-12 columns'> <span class="html-article-menu-option a1" data-line-height="1.5em"> <i class="fa"></i> </span> <span class="html-article-menu-option a2" data-line-height="1.8em"> <i class="fa"></i> </span> <span class="html-article-menu-option a3" data-line-height="2.1em"> <i class="fa"></i> </span> </div> </div> </div> <div class='html-column-width large-6 medium-6 small-12 columns'> <div class='row'> <div class='html-font-label large-4 medium-4 small-12 columns' >Column Width:</div> <div class='large-8 medium-8 small-12 columns'> <span class="html-article-menu-option a1" data-column-width="20%"> <i class="fa"></i> </span> <span class="html-article-menu-option a2" data-column-width="10%"> <i class="fa"></i> </span> <span class="html-article-menu-option a3" data-column-width="0%"> <i class="fa"></i> </span> </div> </div> </div> </div> <div class='row'> <div class='html-font-bg large-6 medium-6 small-12 columns end'> <div class='row'> <div class='html-font-label large-4 medium-4 small-12 columns'>Background:</div> <div class='large-8 medium-8 small-12 columns'> <div class="html-article-menu-option html-nav-bg html-nav-bright" data-bg="bright"> <i class="fa fa-file-text"></i> </div> <div class="html-article-menu-option html-nav-bg html-nav-dark" data-bg="dark"> <i class="fa fa-file-text-o"></i> </div> <div class="html-article-menu-option html-nav-bg html-nav-creme" data-bg="creme"> <i class="fa fa-file-text"></i> </div> </div> </div> </div> </div> </div> </div> <article ><div class='html-article-content'> <span itemprop="publisher" content="Multidisciplinary Digital Publishing Institute"></span><span itemprop="url" content="https://www.mdpi.com/1420-3049/27/3/1071"></span> <div class="article-icons"><span class="label openaccess" data-dropdown="drop-article-label-openaccess" aria-expanded="false">Open Access</span><span class='label choice' data-dropdown='drop-article-label-choice' aria-expanded='false' data-editorschoiceaddition='<a href="/journal/molecules/editors_choice">More Editor’s choice articles in journal <em>Molecules</em>.</a>'>Editor’s Choice</span><span class="label articletype">Article</span></div> <h1 class="title hypothesis_container" itemprop="name"> Investigating the Broad Matrix-Gate Network in the Mitochondrial ADP/ATP Carrier through Molecular Dynamics Simulations </h1> <div class="art-authors hypothesis_container"> by <span class="inlineblock "><div class='profile-card-drop' data-dropdown='profile-card-drop6923614' data-options='is_hover:true, hover_timeout:5000'> Shihao Yao</div><div id="profile-card-drop6923614" data-dropdown-content class="f-dropdown content profile-card-content" aria-hidden="true" tabindex="-1"><div class="profile-card__title"><div class="sciprofiles-link" style="display: inline-block"><div class="sciprofiles-link__link"><img class="sciprofiles-link__image" src="/bundles/mdpisciprofileslink/img/unknown-user.png" style="width: auto; height: 16px; border-radius: 50%;"><span class="sciprofiles-link__name">Shihao Yao</span></div></div></div><div class="profile-card__buttons" style="margin-bottom: 10px;"><a href="https://sciprofiles.com/profile/1937482?utm_source=mdpi.com&utm_medium=website&utm_campaign=avatar_name" class="button button--color-inversed" target="_blank"> SciProfiles </a><a href="https://scilit.com/scholars?q=Shihao%20Yao" class="button button--color-inversed" target="_blank"> Scilit </a><a href="https://www.preprints.org/search?search1=Shihao%20Yao&field1=authors" class="button button--color-inversed" target="_blank"> Preprints.org </a><a href="https://scholar.google.com/scholar?q=Shihao%20Yao" class="button button--color-inversed" target="_blank" rels="noopener noreferrer"> Google Scholar </a></div></div><sup> 1,2,†</sup><span style="display: inline; margin-left: 5px;"></span><a class="toEncode emailCaptcha visibility-hidden" data-author-id="6923614" href="/cdn-cgi/l/email-protection#1f307c717b327c78763073307a727e7673326f6d706b7a7c6b7670713c2f2f2f2f2c2e2f282f2f2f262f2e2f2a2f2b282e2b7d2a7d2b2b2e792a2b2a2a2b2b2e792a2d2a79"><sup><i class="fa fa-envelope-o"></i></sup></a><a href="https://orcid.org/0000-0001-6267-9176" target="_blank" rel="noopener noreferrer"><img src="https://pub.mdpi-res.com/img/design/orcid.png?0465bc3812adeb52?1739526160" title="ORCID" style="position: relative; width: 13px; margin-left: 3px; max-width: 13px !important; height: auto; top: -5px;"></a>, </span><span class="inlineblock "><div class='profile-card-drop' data-dropdown='profile-card-drop6923616' data-options='is_hover:true, hover_timeout:5000'> Boyuan Ma</div><div id="profile-card-drop6923616" data-dropdown-content class="f-dropdown content profile-card-content" aria-hidden="true" tabindex="-1"><div class="profile-card__title"><div class="sciprofiles-link" style="display: inline-block"><div class="sciprofiles-link__link"><img class="sciprofiles-link__image" src="/bundles/mdpisciprofileslink/img/unknown-user.png" style="width: auto; height: 16px; border-radius: 50%;"><span class="sciprofiles-link__name">Boyuan Ma</span></div></div></div><div class="profile-card__buttons" style="margin-bottom: 10px;"><a href="https://sciprofiles.com/profile/2407404?utm_source=mdpi.com&utm_medium=website&utm_campaign=avatar_name" class="button button--color-inversed" target="_blank"> SciProfiles </a><a href="https://scilit.com/scholars?q=Boyuan%20Ma" class="button button--color-inversed" target="_blank"> Scilit </a><a href="https://www.preprints.org/search?search1=Boyuan%20Ma&field1=authors" class="button button--color-inversed" target="_blank"> Preprints.org </a><a href="https://scholar.google.com/scholar?q=Boyuan%20Ma" class="button button--color-inversed" target="_blank" rels="noopener noreferrer"> Google Scholar </a></div></div><sup> 1,2,†</sup><span style="display: inline; margin-left: 5px;"></span><a class="toEncode emailCaptcha visibility-hidden" data-author-id="6923616" href="/cdn-cgi/l/email-protection#ad82cec3c980cecac482c182c8c0ccc4c180dddfc2d9c8ced9c4c2c38e9d9d9d9c9e9c9d9e9d949d9f9d999a9c99cf98cf99999ccb9899989899999ccb989f98cb"><sup><i class="fa fa-envelope-o"></i></sup></a>, </span><span class="inlineblock "><div class='profile-card-drop' data-dropdown='profile-card-drop6923619' data-options='is_hover:true, hover_timeout:5000'> Qiuzi Yi</div><div id="profile-card-drop6923619" data-dropdown-content class="f-dropdown content profile-card-content" aria-hidden="true" tabindex="-1"><div class="profile-card__title"><div class="sciprofiles-link" style="display: inline-block"><div class="sciprofiles-link__link"><img class="sciprofiles-link__image" src="/bundles/mdpisciprofileslink/img/unknown-user.png" style="width: auto; height: 16px; border-radius: 50%;"><span class="sciprofiles-link__name">Qiuzi Yi</span></div></div></div><div class="profile-card__buttons" style="margin-bottom: 10px;"><a href="https://sciprofiles.com/profile/2349881?utm_source=mdpi.com&utm_medium=website&utm_campaign=avatar_name" class="button button--color-inversed" target="_blank"> SciProfiles </a><a href="https://scilit.com/scholars?q=Qiuzi%20Yi" class="button button--color-inversed" target="_blank"> Scilit </a><a href="https://www.preprints.org/search?search1=Qiuzi%20Yi&field1=authors" class="button button--color-inversed" target="_blank"> Preprints.org </a><a href="https://scholar.google.com/scholar?q=Qiuzi%20Yi" class="button button--color-inversed" target="_blank" rels="noopener noreferrer"> Google Scholar </a></div></div><sup> 1,2</sup><span style="display: inline; margin-left: 5px;"></span><a class="toEncode emailCaptcha visibility-hidden" data-author-id="6923619" href="/cdn-cgi/l/email-protection#5e713d303a733d39377132713b333f3732732e2c312a3b3d2a3731307d6e6e6e6d6d6c6e6b6e6d6e3f6e6a6e686e6f696c6a666b666a696f3d6b696b686a696f3d6b6f6b3d"><sup><i class="fa fa-envelope-o"></i></sup></a>, </span><span class="inlineblock "><div class='profile-card-drop' data-dropdown='profile-card-drop6923621' data-options='is_hover:true, hover_timeout:5000'> Min-Xin Guan</div><div id="profile-card-drop6923621" data-dropdown-content class="f-dropdown content profile-card-content" aria-hidden="true" tabindex="-1"><div class="profile-card__title"><div class="sciprofiles-link" style="display: inline-block"><div class="sciprofiles-link__link"><img class="sciprofiles-link__image" src="/bundles/mdpisciprofileslink/img/unknown-user.png" style="width: auto; height: 16px; border-radius: 50%;"><span class="sciprofiles-link__name">Min-Xin Guan</span></div></div></div><div class="profile-card__buttons" style="margin-bottom: 10px;"><a href="https://sciprofiles.com/profile/604205?utm_source=mdpi.com&utm_medium=website&utm_campaign=avatar_name" class="button button--color-inversed" target="_blank"> SciProfiles </a><a href="https://scilit.com/scholars?q=Min-Xin%20Guan" class="button button--color-inversed" target="_blank"> Scilit </a><a href="https://www.preprints.org/search?search1=Min-Xin%20Guan&field1=authors" class="button button--color-inversed" target="_blank"> Preprints.org </a><a href="https://scholar.google.com/scholar?q=Min-Xin%20Guan" class="button button--color-inversed" target="_blank" rels="noopener noreferrer"> Google Scholar </a></div></div><sup> 1,2,*</sup><span style="display: inline; margin-left: 5px;"></span><a class="toEncode emailCaptcha visibility-hidden" data-author-id="6923621" href="/cdn-cgi/l/email-protection#cee1ada0aae3ada9a7e1a2e1aba3afa7a2e3bebca1baabadbaa7a1a0edfefefeaff8f9feabfef7ffa8feabfef7fba8fba8fcf9ffaafeaafffcfaf7fefcfefdfffcfaf7fefafef7"><sup><i class="fa fa-envelope-o"></i></sup></a><a href="https://orcid.org/0000-0001-5067-6736" target="_blank" rel="noopener noreferrer"><img src="https://pub.mdpi-res.com/img/design/orcid.png?0465bc3812adeb52?1739526160" title="ORCID" style="position: relative; width: 13px; margin-left: 3px; max-width: 13px !important; height: auto; top: -5px;"></a> and </span><span class="inlineblock "><div class='profile-card-drop' data-dropdown='profile-card-drop6923623' data-options='is_hover:true, hover_timeout:5000'> Xiaohui Cang</div><div id="profile-card-drop6923623" data-dropdown-content class="f-dropdown content profile-card-content" aria-hidden="true" tabindex="-1"><div class="profile-card__title"><div class="sciprofiles-link" style="display: inline-block"><div class="sciprofiles-link__link"><img class="sciprofiles-link__image" src="/bundles/mdpisciprofileslink/img/unknown-user.png" style="width: auto; height: 16px; border-radius: 50%;"><span class="sciprofiles-link__name">Xiaohui Cang</span></div></div></div><div class="profile-card__buttons" style="margin-bottom: 10px;"><a href="https://sciprofiles.com/profile/1897402?utm_source=mdpi.com&utm_medium=website&utm_campaign=avatar_name" class="button button--color-inversed" target="_blank"> SciProfiles </a><a href="https://scilit.com/scholars?q=Xiaohui%20Cang" class="button button--color-inversed" target="_blank"> Scilit </a><a href="https://www.preprints.org/search?search1=Xiaohui%20Cang&field1=authors" class="button button--color-inversed" target="_blank"> Preprints.org </a><a href="https://scholar.google.com/scholar?q=Xiaohui%20Cang" class="button button--color-inversed" target="_blank" rels="noopener noreferrer"> Google Scholar </a></div></div><sup> 1,2,*</sup><span style="display: inline; margin-left: 5px;"></span><a class="toEncode emailCaptcha visibility-hidden" data-author-id="6923623" href="/cdn-cgi/l/email-protection#200f434e440d4347490f4c0f454d41494c0d50524f54454354494f4e03101011101718114211191116114613181012111210441516114411431044151611421116"><sup><i class="fa fa-envelope-o"></i></sup></a><a href="https://orcid.org/0000-0003-0944-7012" target="_blank" rel="noopener noreferrer"><img src="https://pub.mdpi-res.com/img/design/orcid.png?0465bc3812adeb52?1739526160" title="ORCID" style="position: relative; width: 13px; margin-left: 3px; max-width: 13px !important; height: auto; top: -5px;"></a></span> </div> <div class="nrm"></div> <span style="display:block; height:6px;"></span> <div></div> <div style="margin: 5px 0 15px 0;" class="hypothesis_container"> <div class="art-affiliations"> <div class="affiliation "> <div class="affiliation-item"><sup>1</sup></div> <div class="affiliation-name ">Division of Medical Genetics and Genomics, The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China</div> </div> <div class="affiliation "> <div class="affiliation-item"><sup>2</sup></div> <div class="affiliation-name ">Institute of Genetics, and Department of Genetics, Zhejiang University School of Medicine, Hangzhou 310058, China</div> </div> <div class="affiliation"> <div class="affiliation-item"><sup>*</sup></div> <div class="affiliation-name ">Authors to whom correspondence should be addressed. </div> </div> <div class="affiliation"> <div class="affiliation-item"><sup>†</sup></div> <div class="affiliation-name ">These authors contributed equally to this work.</div> </div> </div> </div> <div class="bib-identity" style="margin-bottom: 10px;"> <em>Molecules</em> <b>2022</b>, <em>27</em>(3), 1071; <a href="https://doi.org/10.3390/molecules27031071">https://doi.org/10.3390/molecules27031071</a> </div> <div class="pubhistory" style="font-weight: bold; padding-bottom: 10px;"> <span style="display: inline-block">Submission received: 14 January 2022</span> / <span style="display: inline-block">Accepted: 1 February 2022</span> / <span style="display: inline-block">Published: 5 February 2022</span> </div> <div class="belongsTo" style="margin-bottom: 10px;"> (This article belongs to the Special Issue <a href=" /journal/molecules/special_issues/Dynamics_Simulation ">Molecular Dynamics Simulations: Advances and Applications</a>)<br/> </div> <div class="highlight-box1"> <div class="download"> <a class="button button--color-inversed button--drop-down" data-dropdown="drop-download-742771" aria-controls="drop-supplementary-742771" aria-expanded="false"> Download <i class="material-icons">keyboard_arrow_down</i> </a> <div id="drop-download-742771" class="f-dropdown label__btn__dropdown label__btn__dropdown--button" data-dropdown-content aria-hidden="true" tabindex="-1"> <a class="UD_ArticlePDF" href="/1420-3049/27/3/1071/pdf?version=1644059024" data-name="Investigating the Broad Matrix-Gate Network in the Mitochondrial ADP/ATP Carrier through Molecular Dynamics Simulations" data-journal="molecules">Download PDF</a> <br/> <a id="js-pdf-with-cover-access-captcha" href="#" data-target="/1420-3049/27/3/1071/pdf-with-cover" class="accessCaptcha">Download PDF with Cover</a> <br/> <a id="js-xml-access-captcha" href="#" data-target="/1420-3049/27/3/1071/xml" class="accessCaptcha">Download XML</a> <br/> <a href="/1420-3049/27/3/1071/epub" id="epub_link">Download Epub</a> <br/> <a href="javascript:void(0);" data-reveal-id="supplementaryModal">Download Supplementary Material</a> <br/> </div> <div class="js-browse-figures" style="display: inline-block;"> <a href="#" class="button button--color-inversed margin-bottom-10 openpopupgallery UI_BrowseArticleFigures" data-target='article-popup' data-counterslink = "https://www.mdpi.com/1420-3049/27/3/1071/browse" >Browse Figures</a> </div> <div id="article-popup" class="popupgallery" style="display: inline; line-height: 200%"> <a href="https://pub.mdpi-res.com/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g001.png?1644059135" title=" <strong>Figure 1</strong><br/> <p>The schematic diagram of AAC’s tripartite structure and function. (<b>a</b>) AAC’s tripartite structure. Three domains of AAC are colored in grey, yellow and blue, respectively. (<b>b</b>) The schematic diagram of AAC’s function. The c-state (PDB: 1OKC [<a href="#B8-molecules-27-01071" class="html-bibr">8</a>]) and m-state (PDB: 6GCI [<a href="#B15-molecules-27-01071" class="html-bibr">15</a>]) AAC are shown in cartoon. ADP and ATP are shown in spheres. (<b>c</b>) The broad matrix gate in the c-state AAC. The charged residues from the Px[DE]xx[KR] motifs are shown as light pink spheres, and the non-motif charged residues are colored as magenta.</p> "> </a> <a href="https://pub.mdpi-res.com/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g002.png?1644059135" title=" <strong>Figure 2</strong><br/> <p>The m-gate electrostatic network in the various mutants (<b>a</b>,<b>c</b>–<b>f</b>) and wild-type (<b>b</b>) of apo AAC. Yellow dash lines are added manually to indicate the salt bridges and H-bonds that do not appear in the shown snapshots. Salt bridges or H-bonds with the occupancies lower than 5% are not shown. For mutants, occupancies of salt bridges and H-bonds are calculated on each trajectory from 200 ns to 1 μs. The occupancies in the <span class="html-italic">wild-type AAC</span> were averaged over last 2 μs of the three 3-μs trajectories.</p> "> </a> <a href="https://pub.mdpi-res.com/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g003.png?1644059135" title=" <strong>Figure 3</strong><br/> <p>The m-gate electrostatic network in the AAC-CATR complex. Top view (<b>a</b>) and side view (<b>b</b>) of the AAC-CATR interactions in the last simulation snapshot (1 μs). CATR is shown in yellow think sticks. In the side-view figure, protein backbones are shown in transparent cartoon. Yellow dash lines are added manually to indicate the H-bonds that do not appear in the shown snapshot. Q36 forms H-bond with both D231 (occupancy: 71%) and K32 (occupancy: 94%), and these values are not labeled in the figure because of limited space. The H-bonds with the occupancies lower than 5% are not shown. The occupancies are calculated on the trajectory from 200 ns to 1 μs. (<b>c</b>) A schematic representation of the CATR-AAC interactions. The electrostatic interactions between CATR and AAC are shown in cyan lines, and the interactions within the m-gate network are shown in blue lines.</p> "> </a> <a href="https://pub.mdpi-res.com/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g004.png?1644059135" title=" <strong>Figure 4</strong><br/> <p>Conformations of R137 are quite different with and without presence of CATR. In the crystal structure (<b>a</b>) and the MD simulation structure (<b>b</b>) of CATR-AAC complex, the guanidine group of R137 binds with backbone carbonyl of R71 and fills the gap between the [YWF][KR]G motif and A26. (<b>c</b>) The gap between the [YWF][KR]G motif and A26 is filled with water molecules in the simulations on apo AAC (<span class="html-italic">wild-type AAC</span>). (<b>d</b>) Sequence logo of A26 and residues involved in the interaction between the [YWF][KR]G motif and Pro kink region in orthologs of AAC, SLC25A42, GDC (graves disease carrier), SCaMC (calcium-binding mitochondrial carrier protein), SLC25A41 and SLC25A43, respectively. Equivalent positions among these paralogs are aligned in the same column. The multiple sequence alignment of SLC25A43 was calculated based on 171 sequences from the UniProt database. The results of other carriers were obtained from our recent work [<a href="#B17-molecules-27-01071" class="html-bibr">17</a>]. The residues are numbered based on hAAC1 (human ADP/ATP carrier), SLC25A42, SLC25A16, SCaMC1, SLC25A41 and SLC25A43, respectively.</p> "> </a> <a href="https://pub.mdpi-res.com/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g005.png?1644059135" title=" <strong>Figure 5</strong><br/> <p>Structures and dynamics of AAC were not significantly affected in the <span class="html-italic">all3A-AAC</span>, <span class="html-italic">R235A-AAC</span> and <span class="html-italic">R279A-AAC</span> mutants. (<b>a</b>–<b>c</b>) RMSF of three mutants compared to that of <span class="html-italic">wild-type AAC</span>. The RMSF were calculated on each trajectory from 200 ns to 1 μs. (<b>d</b>–<b>f</b>) Superposition of the structures at the end of the simulation (1 μs) to the crystal structure (PDB:1OKC).</p> "> </a> <a href="https://pub.mdpi-res.com/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g006.png?1644059135" title=" <strong>Figure 6</strong><br/> <p>The R79A mutation causes drastic conformational change around C1 loop. (<b>a</b>) RMSF of the mutant compared to that of <span class="html-italic">wild-type AAC</span>. The RMSF were calculated on each trajectory from 200 ns to 1 μs. (<b>b</b>) Superposition of the structures at the end of the simulations of <span class="html-italic">R79A-AAC</span> and <span class="html-italic">wild-type AAC</span> (1.5 μs). (<b>c</b>) Time evolution of the minimum distance between R104 and D195 heavy atoms during the simulations. (<b>d</b>) A big crevice formed between the cytoplasmic halves of H3 and H4.</p> "> </a> <a href="https://pub.mdpi-res.com/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g007.png?1644059135" title=" <strong>Figure 7</strong><br/> <p>Changes in the structure and dynamics in <span class="html-italic">all4A-AAC</span>. (<b>a</b>) Superposition of the structures at the end of the simulation (1 μs) to the crystal structure (PDB: 1OKC). The H2, C1 loop, H3 and M2 loop of the simulated structure are present in cartoon mode and highlighted in orange. (<b>b</b>) RMSF of <span class="html-italic">all4A-AAC</span> compared to that of <span class="html-italic">wild-type AAC</span>. The RMSF were calculated on each trajectory from 200 ns to 1 μs. (<b>c</b>) A crevice formed between the matrix end of H3 and the β-turn structure of the [YWF][KR]G motif which allows for the passing through of the solvent. (<b>d</b>) The crevice between H2 and H3 interface became closed after transient opening.</p> "> </a> <a href="https://pub.mdpi-res.com/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g008.png?1644059135" title=" <strong>Figure 8</strong><br/> <p>Geometrical symmetry around the m-gate level in c-state AAC. (<b>a</b>) The model used to calculate deviations from the C<sub>3</sub>-symmetry score. The triplets used for calculation are shown in spheres. (<b>b</b>) The average ψ values of the <span class="html-italic">wild-type</span> simulation structure and crystal structure of c-state AAC (PDB: 1OKC). (<b>c</b>–<b>h</b>) Time evolution of the geometric symmetry analysis in <span class="html-italic">wild-type AAC</span> and the five mutants. Gradient colors are used to indicate the extent to which each plane deviates from C<sub>3</sub>-symmetry.</p> "> </a> <a href="https://pub.mdpi-res.com/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g009.png?1644059135" title=" <strong>Figure 9</strong><br/> <p>Sequence logo presentation of 53 human mitochondria carriers. Only residues around the m-gate level in odd-numbered helices (<b>left</b>) and even-numbered helices (<b>right</b>) are shown. Triplet positions at least with one charged residue in AAC are highlighted with red arrows.</p> "> </a> </div> <a class="button button--color-inversed" href="/1420-3049/27/3/1071/notes">Versions Notes</a> </div> </div> <div class="responsive-moving-container small hidden" data-id="article-counters" style="margin-top: 15px;"></div> <div class="html-dynamic"> <section> <div class="art-abstract art-abstract-new in-tab hypothesis_container"> <p> <div><section class="html-abstract" id="html-abstract"> <h2 id="html-abstract-title">Abstract</h2><b>:</b> <div class="html-p">The mitochondrial ADP/ATP carrier (AAC) exports ATP and imports ADP through alternating between cytosol-open (c-) and matrix-open (m-) states. The salt bridge networks near the matrix side (m-gate) and cytosol side (c-gate) are thought to be crucial for state transitions, yet our knowledge on these networks is still limited. In the current work, we focus on more conserved m-gate network in the c-state AAC. All-atom molecular dynamics (MD) simulations on a variety of mutants and the CATR-AAC complex have revealed that: (1) without involvement of other positive residues, the charged residues from the three Px[DE]xx[KR] motifs only are prone to form symmetrical inter-helical network; (2) R235 plays a determinant role for the asymmetry in m-gate network of AAC; (3) R235 significantly strengthens the interactions between H3 and H5; (4) R79 exhibits more significant impact on m-gate than R279; (5) CATR promotes symmetry in m-gate mainly through separating R234 from D231 and fixing R79; (6) vulnerability of the H2-H3 interface near matrix side could be functionally important. Our results provide new insights into the highly conserved yet variable m-gate network in the big mitochondrial carrier family.</div> </section> <div id="html-keywords"> <div class="html-gwd-group"><div id="html-keywords-title">Keywords: </div><a href="/search?q=ADP%2FATP+carrier">ADP/ATP carrier</a>; <a href="/search?q=mitochondrial+carrier+family">mitochondrial carrier family</a>; <a href="/search?q=transporter">transporter</a>; <a href="/search?q=molecular+dynamics+simulation">molecular dynamics simulation</a></div> <div> </div> </div> </div> </p> </div> </section> </div> <div class="hypothesis_container"> <ul class="menu html-nav" data-prev-node="#html-quick-links-title"> </ul> <div class="html-body"> <section id='sec1-molecules-27-01071' type='intro'><h2 data-nested='1'> 1. Introduction</h2><div class='html-p'>Mitochondria, well known as the “powerhouses of the cell”, are major places to synthesize ATP through oxidative phosphorylation (OXPHOS) in eukaryotes. Mitochondria also synthesize heme and steroid hormones, and house multiple important metabolic pathways including tricarboxylic acid cycle, urea cycle and β-oxidation. In addition, as the semi-autonomous organelles, mitochondria need to replicate their own DNA, and transcribe and translate genes they carry. To fulfill these functions, solutes including ions, nucleotides, amino acids, fatty acids and many other important metabolites need to be continuously exchanged between cytoplasm and mitochondrial matrix. Members of the mitochondrial carrier family (MCF) facilitate transport of these substrates across the highly impermeable inner mitochondrial membrane (IMM) [<a href="#B1-molecules-27-01071" class="html-bibr">1</a>,<a href="#B2-molecules-27-01071" class="html-bibr">2</a>,<a href="#B3-molecules-27-01071" class="html-bibr">3</a>].</div><div class='html-p'>Although substrates transported by mitochondrial carriers (MCs) are extremely diversified, these transporters all have three homologous domains (<a href="#molecules-27-01071-f001" class="html-fig">Figure 1</a>a), and each domain contains many conserved sequence motifs such as [YF][DE]xx[RK], GxxxG and πxxxπ motifs [<a href="#B3-molecules-27-01071" class="html-bibr">3</a>] near the cytoplasmic side of the carriers and more conserved MCF motif near the matrix side: Px[DE]xx[KR]xRxxQ-(matrix loop)-[YF]xG-(matrix helix)-[DE]Gxxxx[YWF][KR]G [<a href="#B2-molecules-27-01071" class="html-bibr">2</a>,<a href="#B3-molecules-27-01071" class="html-bibr">3</a>,<a href="#B4-molecules-27-01071" class="html-bibr">4</a>]. The special tripartite symmetry in sequence and highly conserved MCF motif in each homologous domain distinguish this family from other transporter families. Therefore, sequence symmetry analysis is important to understand transport mechanism of this family [<a href="#B5-molecules-27-01071" class="html-bibr">5</a>], and residues at the three symmetric positions in the tripartite structure are usually referred to as triplets [<a href="#B6-molecules-27-01071" class="html-bibr">6</a>]. Currently, 53 members have been identified in human MCF. This family represents the biggest solute carrier (SLC) subfamily and is also known as SLC25.</div><div class='html-p'>Mitochondrial ADP/ATP carrier (AAC, also named ANT for adenine nucleotide translocase) is paradigm of the MCF family and is the most abundant protein in IMM [<a href="#B7-molecules-27-01071" class="html-bibr">7</a>]. It imports ADP into the mitochondrial matrix and exports ATP to the cytosol through cycling between the cytosolic-open (c-) state and matrix-open (m-) state upon ligand binding (<a href="#molecules-27-01071-f001" class="html-fig">Figure 1</a>b). AAC is currently the only MCF member whose crystal structures have been resolved. The c-state structure was resolved through co-crystallizing with the specific inhibitor carboxyatractyloside (CATR) [<a href="#B8-molecules-27-01071" class="html-bibr">8</a>,<a href="#B9-molecules-27-01071" class="html-bibr">9</a>]. The structure exhibits three-fold pseudo-symmetry, with each structurally similar domain containing two transmembrane helices connected by a short amphipathic helix at the matrix end (domain 1: H1-h12-H2, domain 2: H3-h34-H4, domain 3: H5-h56-H6). Proline within the extremely conserved Px[DE]xx[KR] motif introduces a sharp kink in each odd-numbered helix, and the six transmembrane helices surround a big pocket opened towards the cytosol. The six charged residues from the three Px[DE]xx[KR] motifs form a symmetrical and cyclic inter-helical salt bridge network on the matrix side (<a href="#molecules-27-01071-f001" class="html-fig">Figure 1</a>c). This network was called matrix-gate or m-gate [<a href="#B10-molecules-27-01071" class="html-bibr">10</a>,<a href="#B11-molecules-27-01071" class="html-bibr">11</a>], and it was proposed that the m-gate is an important factor to stabilize the c-state conformation of AAC.</div><div class='html-p'>At the m-gate level, other basic residues also appear within the pocket of AAC: K22, R79, R279 and R235, and these residues bind directly or indirectly through water molecules with the inhibitor CATR in the crystal structure. For simplicity, we denote these basic residues in the pocket that do not belong to the Px[DE]xx[KR] motif as “non-motif” basic residues in the current work (<a href="#molecules-27-01071-f001" class="html-fig">Figure 1</a>c), although they may also involve in some motif that has not be recognized. CATR is structurally different and much bulkier than ADP, the natural substrate of c-state AAC. Therefore, it was pointed out that CATR binding might rearrange the salt bridge network and deviate the crystal structure from the natural conformation of either ADP-bound or apo AAC [<a href="#B7-molecules-27-01071" class="html-bibr">7</a>]. Various molecular dynamics (MD) simulations on apo c-state AAC did show that the overall salt-bridge network at the bottom of the cavity rearranged after removing CATR [<a href="#B4-molecules-27-01071" class="html-bibr">4</a>,<a href="#B12-molecules-27-01071" class="html-bibr">12</a>,<a href="#B13-molecules-27-01071" class="html-bibr">13</a>,<a href="#B14-molecules-27-01071" class="html-bibr">14</a>]. More specifically, our previous simulations on microsecond time scale have shown that when the inhibitor CATR is removed, the charged residues from the Px[DE]xx[KR] sequence mainly form intra-helical salt bridges, and together with polar residues and non-motif positive residues including K79, R235 and R279, form a broad asymmetric electrostatic network at the bottom of the pocket [<a href="#B4-molecules-27-01071" class="html-bibr">4</a>]. In this broad asymmetric network, domains 2 and 3 bind strongly together, while domain 1 only binds loosely with the other two domains. Most strikingly, the asymmetry in this broad m-gate network matches with the recently resolved m-state crystal structure in which domain 1 deviates from the other two domains in the matrix side [<a href="#B15-molecules-27-01071" class="html-bibr">15</a>]. The partially asymmetric m-state structure was also justified by the asymmetry in the three specific cardiolipin binding sites at the domain-domain interfaces observed in our previous MD simulations [<a href="#B16-molecules-27-01071" class="html-bibr">16</a>]. Our previous work implies that m-gate network provides important clues to understand the transport mechanism of AAC.</div><div class='html-p'>Our previous results suggest that the non-motif positive residues R79, R235 and R279 are integral part of the broad m-gate network. However, the effect of these residues on the m-gate and the structural dynamics of AAC are unclear. In the current work, we carried out all-atom MD simulations on CATR-bound AAC and the five mutants of apo AAC in which different non-motif positive residues at the m-gate level are mutated to alanine. Through comparing the m-gate network and the structural dynamics of the mutants to those of wild-type apo AAC, we aim to understand how these non-motif residues may contribute to the m-gate profile and affect structural dynamics of the carrier. As CATR binds with both motif and non-motif positive residues, elucidating roles of the non-motif residues on the m-gate network also help clarify how CATR binding may affect this broad network.</div><div class="html-fig-wrap" id="molecules-27-01071-f001"> <div class='html-fig_img'> <div class="html-figpopup html-figpopup-link" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/27/3/1071/display" href="#fig_body_display_molecules-27-01071-f001"> <img alt="Molecules 27 01071 g001 550" data-large="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g001.png" data-original="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g001.png" data-lsrc="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g001-550.jpg" /> <a class="html-expand html-figpopup" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/27/3/1071/display" href="#fig_body_display_molecules-27-01071-f001"></a> </div> </div> <div class="html-fig_description"> <b>Figure 1.</b> The schematic diagram of AAC’s tripartite structure and function. (<b>a</b>) AAC’s tripartite structure. Three domains of AAC are colored in grey, yellow and blue, respectively. (<b>b</b>) The schematic diagram of AAC’s function. The c-state (PDB: 1OKC [<a href="#B8-molecules-27-01071" class="html-bibr">8</a>]) and m-state (PDB: 6GCI [<a href="#B15-molecules-27-01071" class="html-bibr">15</a>]) AAC are shown in cartoon. ADP and ATP are shown in spheres. (<b>c</b>) The broad matrix gate in the c-state AAC. The charged residues from the Px[DE]xx[KR] motifs are shown as light pink spheres, and the non-motif charged residues are colored as magenta.  </div> </div> <div class="html-fig_show mfp-hide" id ="fig_body_display_molecules-27-01071-f001" > <div class="html-caption" > <b>Figure 1.</b> The schematic diagram of AAC’s tripartite structure and function. (<b>a</b>) AAC’s tripartite structure. Three domains of AAC are colored in grey, yellow and blue, respectively. (<b>b</b>) The schematic diagram of AAC’s function. The c-state (PDB: 1OKC [<a href="#B8-molecules-27-01071" class="html-bibr">8</a>]) and m-state (PDB: 6GCI [<a href="#B15-molecules-27-01071" class="html-bibr">15</a>]) AAC are shown in cartoon. ADP and ATP are shown in spheres. (<b>c</b>) The broad matrix gate in the c-state AAC. The charged residues from the Px[DE]xx[KR] motifs are shown as light pink spheres, and the non-motif charged residues are colored as magenta.</div> <div class="html-img"><img alt="Molecules 27 01071 g001" data-large="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g001.png" data-original="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g001.png" data-lsrc="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g001.png" /></div> </div></section><section id='sec2-molecules-27-01071' type='results'><h2 data-nested='1'> 2. Results</h2><section id='sec2dot1-molecules-27-01071' type=''><h4 class='html-italic' data-nested='2'> 2.1. Impact of Mutations of the Non-Motif Positive Residues on the m-Gate Network</h4><div class='html-p'>To represent the ground state of the m-gate network formed by the charged residues of Px[DE]xx[KR] motif, we built <span class='html-italic'>all4A-AAC</span> mutant in which all the non-motif positive residues of AAC including K22, R79, R235 and R279 were mutated to alanine. MD simulation on this mutant shows that the charged motif residues are more prone to form inter-helical salt bridges than intra-helical salt bridges (<a href="#molecules-27-01071-f002" class="html-fig">Figure 2</a>a and <a href="#app1-molecules-27-01071" class="html-app">Figure S1a</a>). The occupancies of the inter-helical salt bridges E29:R137, D134:R234 and D231:K32 are 78%, 89% and 53%, respectively, and the intra-helical salt bridges E29:K32, D231:R234 and D134:R137 show occupancies of 18%, 18% and 79%, respectively. Our results demonstrate that compared to the <span class='html-italic'>wild-type AAC</span> (<a href="#molecules-27-01071-f002" class="html-fig">Figure 2</a>b and <a href="#app1-molecules-27-01071" class="html-app">Figure S1b</a>), the ground state of the m-gate network is more symmetrical and contains more inter-helical interactions.</div><div class='html-p'>To evaluate how R235 affects the ground state of the m-gate network, we built <span class='html-italic'>all3A-AAC</span> mutant system in which all the four non-motif positive residues except R235 were mutated to alanine, and this can also be viewed as introducing R235 to <span class='html-italic'>all4A-AAC</span>. R235 is the featured residue in AAC and the closely related mitochondrial carriers SLC25A16 (Solute carrier family 25, member 16, graves disease carrier) and SLC25A42. We previously reported the central role of R235 in the asymmetric electrostatic network of the <span class='html-italic'>wild-type AAC</span> [<a href="#B4-molecules-27-01071" class="html-bibr">4</a>]. By comparing the simulation results of <span class='html-italic'>all4A-AAC</span> and <span class='html-italic'>all3A-AAC</span>, we clearly demonstrate how the presence of R235 dramatically changes the m-gate network (<a href="#molecules-27-01071-f002" class="html-fig">Figure 2</a>c and <a href="#app1-molecules-27-01071" class="html-app">Figure S1c</a>). In <span class='html-italic'>all3A-AAC</span>, R235 forms very strong salt bridges with both D134 and D231. This destroys the inter-helical salt bridge D231:K32, while the intra-helical E29:K32 is dramatically strengthened (occupancy: 97%). Meanwhile, R234 forms π-π stacking interaction with R235, which destroys intra-helical salt bridge D231:R234 and strengthens inter-helical salt bridge D134:R234. It’s apparent that the presence of R235 greatly strengthens both intra-helical salt bridges within H3 or H5 and an inter-helical salt bridge between them, while the inter-helical salt bridges between H1 and the other two helices are dramatically weakened. Therefore, our results suggest that R235 is the key determinant for the high asymmetry in the m-gate network.</div><div class='html-p'>To assess the effect of introducing R79 to the above <span class='html-italic'>all3A-AAC</span> mutant, the <span class='html-italic'>R279A-AAC</span> mutant was built in which both R279 and K22 of AAC were mutated to alanine. The MD simulations show that the presence of R79 lifts up D134 through forming the D134:R79 salt bridge. This does not change the strong D134:R235 salt bridge but deteriorates the D134:R234 salt bridge. R234 changes the orientation to bind with D231 and S179 simultaneously (<a href="#molecules-27-01071-f002" class="html-fig">Figure 2</a>d and <a href="#app1-molecules-27-01071" class="html-app">Figure S1d</a>). The conformation of R234 in <span class='html-italic'>R279A-AAC</span> is quite similar to that in the <span class='html-italic'>wild-type AAC</span> (<a href="#molecules-27-01071-f002" class="html-fig">Figure 2</a>b and <a href="#app1-molecules-27-01071" class="html-app">Figure S1b</a>). Meanwhile, the effect of R79 on the matrix-gate network can also be evaluated by comparing the simulations results of <span class='html-italic'>wild-type AAC</span> and <span class='html-italic'>R79A-AAC</span> in which both R79 and K22 were mutated to alanine. Compared to <span class='html-italic'>R79A-AAC</span>, in <span class='html-italic'>wild-type AAC</span> the conformation of R234 is drastically changed and the inter-helical D134:R234 salt bridge is destroyed, with occupancy decreased from 100% to 8%. In addition, the inter-helical E29:R137 salt bridge is disrupted and the occupancy dropped from 96% to 27%. Therefore, comparisons between these two pairs of systems lead to consistent results on the effect of R79 to the m-gate network. In brief, R79 drastically deteriorates the inter-helical salt bridge D134:R234 and E29:R137.</div><div class='html-p'>To estimate the impact of introducing R279 to the above <span class='html-italic'>all3A-AAC</span> mutant, the <span class='html-italic'>R79A-AAC</span> mutant was built in which both R79 and K22 of AAC were mutated to alanine. The MD simulations show that R279 forms a stable salt bridge with E29, but it does not bring obvious changes to the m-gate network except that the inter-helical E29:R137 salt bridge is strengthened (occupancy: 96%) (<a href="#molecules-27-01071-f002" class="html-fig">Figure 2</a>e and <a href="#app1-molecules-27-01071" class="html-app">Figure S1e</a>). Comparing the simulations results on <span class='html-italic'>wild-type AAC</span> and <span class='html-italic'>R279A-AAC</span> leads to a similar conclusion: R279 does not drastically change the m-gate network.</div><div class='html-p'>In <span class='html-italic'>R235A-AAC</span>, R235 is mutated to alanine while all the other non-motif charges residues (K22, R79 and R279) were maintained. MD simulations show that in this mutant, R79 forms a very strong salt bridge with D134 and lifts up D134 which weakens both intra-helical salt bridge D134:R137 and inter-helical salt bridge D134:R234. Here, R279 only binds with N276 and does not become involved in the m-gate network. Basically, the m-gate network in R235A-AAC is quite similar to that in all4A-AAC, which is more symmetrical and contains more inter-helical populations. This again highlights the determinant role of R235 in the asymmetry of the m-gate network of AAC. Moreover, whenever R235 appears, the salt bridge connecting H3 and H5 exhibits extremely high occupancy of almost 100% (<a href="#molecules-27-01071-f002" class="html-fig">Figure 2</a>b–e and <a href="#app1-molecules-27-01071" class="html-app">Figure S1b–e</a>). In contrast, the salt bridge between H3 and H5 (D134:R234) shows an occupancy of 89% in <span class='html-italic'>all4A-AAC</span> and occupancy of 49% in <span class='html-italic'>R235A-AAC</span>. These results demonstrate that R235 dramatically strengthen the interactions between H3 and H5.</div></section><section id='sec2dot2-molecules-27-01071' type=''><h4 class='html-italic' data-nested='2'> 2.2. Impact of CATR Binding on the m-Gate Network</h4><div class='html-p'>To investigate the effect of CATR binding to the m-gate network, we ran 1-μs MD simulation on ACC in complex with CATR, and compared the results to those of the wild-type apo AAC and the mutants described above. The m-gate network in the crystal structure is well maintained in the simulation on the <span class='html-italic'>CATR-AAC</span> complex (<a href="#molecules-27-01071-f003" class="html-fig">Figure 3</a>). The central hydroxyl group of CATR forms H-bonds to both D231 and R234 on H5 with high occupancies of 98% and 99%, respectively, and this effectively prevents the formation of intra-helical R234:D231 salt bridge (<a href="#molecules-27-01071-f003" class="html-fig">Figure 3</a>). Moreover, the intervention of the central hydroxyl group of CATR between D231 and R234 pushes D231 closer to H1 and R234 closer to H3, which favors the formation of the inter-helical salt bridges D231:K32 (occupancy: 95%) and D134:R234 (occupancy: 76%), respectively. In fact, D231 forms extensive interactions with K32, Q36, R235 and the central hydroxyl group of CATR, which effectively prevents the formation of the intra-helical E29:K32 salt bridge. In addition to binding with D231 with high occupancy of 99%, R235 also binds with T138 with high occupancy 98%. R235 only binds with D134 occasionally with low occupancy of 19%. R79 binds to the primary carboxyl group of CATR (the only carboxyl group of ATR). In fact, this carboxyl group together with the central hydroxyl group of CATR forms an extensive electrostatic network with R234, Y131, D134 and R79 as in the crystal structure, and this effectively prevents D134 from forming intra-helical salt bridge with R137. This leads to the high occupancy of the inter-helical salt bridge R137:E29 of around 86%. Although R279 is at the equivalent position of R79, it binds to the secondary carboxyl group of CATR a bit more dynamically than R79. In summary, our simulations on the CATR-AAC complex, together with the simulation results on the above mutants, reveal the effect of CATR binding to the m-gate network: CATR promotes symmetry and inter-helical salt bridges in the m-gate network mainly by separating R234 from D231 with its central hydroxyl group and through fixing R79 with its primary carboxyl group. Our results are in agreement with the ability of CATR to lock AAC in the c-state conformation.</div></section><section id='sec2dot3-molecules-27-01071' type=''><h4 class='html-italic' data-nested='2'> 2.3. The Conserved Gap between A26 and the [YWF][KR]G Motif in Domain 1</h4><div class='html-p'>When R137 forms a salt bridge with E29 in the crystal structure or in MD simulations of the CATR-AAC complex, it forms H-bond with the backbone carbonyl group of R71, the middle residue of the conserved [YWF][KR]G motif in domain 1. In this way, the guanidine group of R137 fills the gap formed between the β-turn structure of the [YWF][KR]G motif and the small residue A26 (<a href="#molecules-27-01071-f004" class="html-fig">Figure 4</a>a,b). In contrast, without the presence of CATR in the simulations of apo AAC, R137 moves up to bind with D134, and the gap is filled with solvent molecules (<a href="#molecules-27-01071-f004" class="html-fig">Figure 4</a>c). Here the solvent in the pocket is very close to the solvent from the matrix side, and the only barrier between them is the β-turn structure of the [YWF][KR]G motif. This implies that, due to the presence of A26, the interface of the matrix ends of H2 and H3 could be more vulnerable to ligand binding in the pocket.</div></section><section id='sec2dot4-molecules-27-01071' type=''><h4 class='html-italic' data-nested='2'> 2.4. Impact of Mutations of the Non-Motif Positive Residues on the Structural Dynamics of AAC</h4><div class='html-p'>To further investigate the influence of the above mutations on the structure and dynamics of AAC, we compared the root mean square fluctuation (RMSF) of each mutant system with <span class='html-italic'>wild-type AAC</span>, and superimposed the last snapshot of each simulation on the crystal structure. The 1-μs simulation results show that the <span class='html-italic'>all3A-AAC</span>, <span class='html-italic'>R235A-AAC</span> and <span class='html-italic'>R279A-AAC</span> show quite similar structural dynamics as the <span class='html-italic'>wild-type AAC</span> (<a href="#molecules-27-01071-f005" class="html-fig">Figure 5</a>a–c). The crystal structure conformation is well maintained in these three mutants except that the inward movement of H2 was consistently observed (<a href="#molecules-27-01071-f005" class="html-fig">Figure 5</a>d–f). In <span class='html-italic'>R235A-AAC</span>, a drift of the cytoplasmic half of H1 and backbone bending near the H6 terminal end were also observed (<a href="#molecules-27-01071-f005" class="html-fig">Figure 5</a>e). The bending of H6 was also reported in one simulation of the <span class='html-italic'>wild-type AAC</span> on a longer time scale [<a href="#B4-molecules-27-01071" class="html-bibr">4</a>].</div><div class='html-p'>In <span class='html-italic'>R79A-AAC</span>, significant structural changes were observed at the cytoplasmic side, so we extended the simulation to 1.5 μs. In <span class='html-italic'>wild-type AAC</span>, C1 loop is much more stable than C2 loop as reflected by the much lower RMSF values (<a href="#molecules-27-01071-f006" class="html-fig">Figure 6</a>a), and a major stabilizing factor is the strong D195(H4):R104(C1 loop) salt bridge that attaches C1 loop to H4 (<a href="#molecules-27-01071-f006" class="html-fig">Figure 6</a>b). This salt bridge is extremely stable in the simulations of <span class='html-italic'>wild-type AAC</span>, but it became much more dynamic in <span class='html-italic'>R79A-AAC</span> (<a href="#molecules-27-01071-f006" class="html-fig">Figure 6</a>c). Therefore, the C1 loop together with cytoplasmic sides of H2 and H3 helices are much more flexible in <span class='html-italic'>R79A-AAC</span> as reflected by the dramatic increase in the RMSF values of this region (<a href="#molecules-27-01071-f006" class="html-fig">Figure 6</a>a). Starting at 1193 ns, the dynamic R104:D195 salt bridge completely separated (<a href="#molecules-27-01071-f006" class="html-fig">Figure 6</a>b), forming a big crevice between the cytoplasmic halves of the H3 and H4 helices in <span class='html-italic'>R79A-AAC</span> trajectory (<a href="#molecules-27-01071-f006" class="html-fig">Figure 6</a>d). Moreover, drastic and dynamic distortions are observed within the helix backbone of H3, which is also reflected by the big difference of RMSF values for the H3 region in <span class='html-italic'>R79A-AAC</span> and in <span class='html-italic'>wild-type AAC</span> (<a href="#molecules-27-01071-f006" class="html-fig">Figure 6</a>a).</div><div class='html-p'>In <span class='html-italic'>all4A-AAC</span>, significant structural changes occurred at the matrix side, more specifically, in the M1 loop, M2 loop and the matrix halves of H2 and H3 helices (<a href="#molecules-27-01071-f007" class="html-fig">Figure 7</a>a). When the RMSF curves of <span class='html-italic'>all4A-AAC</span> and <span class='html-italic'>wild-type AAC</span> are compared, a most significant difference is observed in the M2 loop (<a href="#molecules-27-01071-f007" class="html-fig">Figure 7</a>b). In the crystal structures of bovine AAC1, the guanidinium groups of R30, R71 and R151 form a nice stacking structure. In the simulations of <span class='html-italic'>all4A-AAC</span>, the R30:R71:R151 stacking structure became dissociated at 372 ns, and this led to the disruption of the electrostatic interaction between R30 and N-terminus of H3 and also the cyclic electrostatic network (<a href="#app1-molecules-27-01071" class="html-app">Figure S3</a>). In contrast, although the R30:R71:R151 stacking structure also become dissociated with longer simulation time (at around 1.3 μs) in <span class='html-italic'>wild-type</span> AAC, the dissociation of the stacking structure did not lead to the disruption of the cyclic electrostatic network between capping arginines and N-termini of odd-numbered helices (<a href="#app1-molecules-27-01071" class="html-app">Figure S3</a>). The difference highlights the significance of the non-motif positive residues in maintaining the structure of the c-state AAC. Meanwhile, in <span class='html-italic'>all4A-AAC</span> a narrow crevice quickly formed at 380 ns between the matrix ends of H2 and H3, and through this crevice solvent in the pocket went through with the bulk solvent at the matrix side. This narrow crevice became closed at 430 ns, and from 850 ns an even bigger crevice formed at the same interface till the end of the simulation (<a href="#molecules-27-01071-f007" class="html-fig">Figure 7</a>c). These results support the above speculation on the vulnerability of the H2-H3 interface inferred from the simulation results of <span class='html-italic'>wild-type AAC</span>, and also suggest the stabilization role of the R30:R71:R151 stacking structure on the vulnerable H2-H3 interface. To investigate whether the big crevice at the H2-H3 interface will lead to more drastic conformational changes to the carrier, we extended the 1-μs simulation of <span class='html-italic'>all4A-AAC</span> for additional 500 ns. Molecular dynamic simulation results show that the opening of the H2-H3 interface did not lead to more drastic conformational changes, instead, the crevice became closed just before the end of the 1.5-μs simulation (<a href="#molecules-27-01071-f007" class="html-fig">Figure 7</a>d). Results show a strong inclination of AAC to maintain its intact ground c-state conformation, and its transition to the m-state can only be triggered upon ligand binding.</div></section><section id='sec2dot5-molecules-27-01071' type=''><h4 class='html-italic' data-nested='2'> 2.5. Structure-Based Symmetry Analysis near the m-Gate Level</h4><div class='html-p'>Threefold pseudo-symmetry is an important feature of the c-state structure of AAC, and investigations on the relationship between m-gate and structural symmetry near the m-gate level might provide more clues to understand the transport mechanism of AAC. In the previous work on m-state AAC, deviation of each triangle formed by three Cα atoms of each triplet group from an equilateral triangle was used to assess the degree of geometrical symmetry, and more specifically, the metric ψ was calculated through averaging the deviations of the three triangle angles from 60° [<a href="#B18-molecules-27-01071" class="html-bibr">18</a>]. Higher values of ψ indicate a high deviation from C<sub>3</sub> symmetry for the triplet residues. Following the same method, here we analyzed symmetry degree in H1, H3 and H5 near the m-gate level, ranging from triplets 37 to triplets 25 (<a href="#molecules-27-01071-f008" class="html-fig">Figure 8</a>a). We first calculated ψ values for the CATR-inhibited crystal structure (PDB: 1OKC), and compared to the averaged ψ values based on 3 μs MD simulation trajectory of <span class='html-italic'>wild-type AAC</span> (<a href="#molecules-27-01071-f008" class="html-fig">Figure 8</a>b). The results show that in the simulations on <span class='html-italic'>wild-type AAC</span>, triplets 31 to 37 consistently exhibit lower ψ values in simulated apo AAC than in CATR-bound crystal structure, while most of the preceding triplets (triplets 25 to 30) are more symmetrical in the CATR-bound crystal structure than in apo AAC. Due to different progression directions of the three matrix loops, the triplet 37 at the terminal ends of the odd-numbered helices has a very high ψ value in both the crystal structure and in apo AAC. Worthy of special mentioning, the triplet 33 (L33, T138 and R235) also exhibits a much higher deviation in symmetry than the neighboring triplets, and this is consistent with the determinant role of R235 in the asymmetry of the m-gate network as described above. Then we calculated the time evolutions of ψ values of the triplets around the m-gate level in different simulation systems (<a href="#molecules-27-01071-f008" class="html-fig">Figure 8</a>c–h). Compared to <span class='html-italic'>wild-type AAC</span> (<a href="#molecules-27-01071-f008" class="html-fig">Figure 8</a>c), geometrical symmetry in <span class='html-italic'>R</span><span class='html-italic'>279A-AAC</span> and <span class='html-italic'>R235A-AAC</span> systems (<a href="#molecules-27-01071-f008" class="html-fig">Figure 8</a>f,g) is generally improved. Of special interest, in <span class='html-italic'>all4A-AAC</span>, high deviation value was observed after 300 ns (<a href="#molecules-27-01071-f008" class="html-fig">Figure 8</a>d), although the m-gate network in this mutant is more symmetric and has more inter-helical interactions than that in the <span class='html-italic'>wild-type AAC</span> (<a href="#molecules-27-01071-f002" class="html-fig">Figure 2</a>a,b). This result indicates the importance of the non-motif charged residues in maintaining the geometrical symmetry, although these non-motif residues are asymmetrically distributed. Most significantly, the R79A mutation severely deteriorates the geometrical symmetry around the m-gate level since the beginning of the simulation, especially for the triplets 32 and 36 (<a href="#molecules-27-01071-f008" class="html-fig">Figure 8</a>h), and this is mainly caused by the backbone distortions within H3. This result highlights the significance of R79 in maintaining the structural integrity and symmetry of AAC.</div></section></section><section id='sec3-molecules-27-01071' type='discussion'><h2 data-nested='1'> 3. Discussion</h2><div class='html-p'>Compared to most membrane proteins, mitochondrial carriers are featured with significantly large positive net charges [<a href="#B12-molecules-27-01071" class="html-bibr">12</a>]. Within the pocket, in addition to the balanced charges from the Px[DE]xx[KR] motif on odd-numbered helices, positive residues also appear at high frequencies at positions equivalent to the triplet 79 of AAC (<a href="#molecules-27-01071-f009" class="html-fig">Figure 9</a>) on even-numbered helices, and this leads to the net positive charges near the bottom of the pocket. Considering consensus sequence feature at the triplet 79 positions in contrast to the tremendous diversity in structures and charges of the substrates transported by mitochondrial carriers, we infer that the triplet 79 positions could be more related to the general transport mechanism shared by this family, rather than carrying out substrate discrimination function. This inference is also supported by our recent identification of a new highly specific ADP binding site near the upper region of the cavity in c-state AAC [<a href="#B17-molecules-27-01071" class="html-bibr">17</a>].</div><div class='html-p'>In AAC, in addition to R79 and R279 at the triplet 79 positions, R235 within the featured RRRMMM motif also appear at the bottom of the cavity. Our previous work have shown that without presence of the inhibitor CATR, these positive residues together with charged residues of the Px[DE]xx[KR] motifs form a broad asymmetric m-gate network [<a href="#B4-molecules-27-01071" class="html-bibr">4</a>]. The difference between the m-gate networks with and without presence of CATR was also highlighted in earlier MD simulation studies on AAC [<a href="#B13-molecules-27-01071" class="html-bibr">13</a>,<a href="#B19-molecules-27-01071" class="html-bibr">19</a>]. A recent study on the uncoupling protein UCP2 also demonstrated the engagement of the three triplet 79 residues (R88, R185 and R279) in the broad matrix network [<a href="#B20-molecules-27-01071" class="html-bibr">20</a>]. Therefore, results from different groups consistently suggest that these non-motif basic residues are integral part of the broad matrix network. In the current work, through MD simulations on a variety of AAC mutants, contributions from these non-motif positive residues on the profile of m-gate network and structural dynamics of AAC were assessed.</div><div class='html-p'>Our findings suggest that R235 is the key residue that determines the asymmetry of the m-gate network, and it also dramatically strengthens the interactions between H3 and H5 (<a href="#molecules-27-01071-f002" class="html-fig">Figure 2</a> and <a href="#app1-molecules-27-01071" class="html-app">Figure S1</a>). In the partially asymmetric crystal structure of m-state AAC, domain 2 and domain 3 still attach together at the matrix side when domain 1 separates from these two domains. This implies the importance of R235 in holding domains 2 and 3 together during state transitions. In the previous studies, R253I mutation in yeast AAC2 results in loss of function of the carrier (corresponding to R235 in bovine AAC1) [<a href="#B21-molecules-27-01071" class="html-bibr">21</a>,<a href="#B22-molecules-27-01071" class="html-bibr">22</a>].</div><div class='html-p'>Although R79 and R279 are at equivalent positions in homologous domains 1 and 3, they play quite different roles in affecting the m-gate network. Our results show that through forming a salt bridge with D134, R79 promotes intra-helical D231:R234 and weakens inter-helical salt bridges D134:R234 and E29:R137. Although R279 also forms a stable salt bridge with E29 in both <span class='html-italic'>wild-type AAC</span> and <span class='html-italic'>R79A-AAC</span>, R279 does not significantly change the m-gate network, which is different from our previous speculation [<a href="#B4-molecules-27-01071" class="html-bibr">4</a>]. The less impact of R279 on the m-gate network is consistent with the previous experiment in which the R279A mutant still retained good transport activity and high expression level, while R79A mutation led to loss of function of the carrier [<a href="#B22-molecules-27-01071" class="html-bibr">22</a>]. R79H mutation was also reported to cause severe early-onset dominant mitochondrial disease [<a href="#B23-molecules-27-01071" class="html-bibr">23</a>].</div><div class='html-p'>Our results suggest that the inhibitor CATR promotes symmetrical m-gate network mainly through separating R234 from D231 and fixing R79. CATR binds with R79 through its primary carboxyl group that is also shared by atractyloside (ATR). The less impact of R279 on m-gate network also helps explain why ATR that does not have secondary carboxyl group to bind with R279 can still stabilize and inhibit the c-state AAC effectively.</div><div class='html-p'>K22 is also an important positive residue within the pocket of AAC and its physiological significance has been confirmed by mutagenesis [<a href="#B21-molecules-27-01071" class="html-bibr">21</a>] and acetylation experiments [<a href="#B24-molecules-27-01071" class="html-bibr">24</a>,<a href="#B25-molecules-27-01071" class="html-bibr">25</a>]. However, K22 does not become involved in forming salt bridges with other residues in <span class='html-italic'>wild-type</span> apo AAC [<a href="#B4-molecules-27-01071" class="html-bibr">4</a>], and therefore we did not investigate the impact of K22 in the current work. MD simulations on ADP binding process suggest that K22 might help catch the ADP detached from the specific binding site and relay it to the central binding site [<a href="#B17-molecules-27-01071" class="html-bibr">17</a>].</div><div class='html-p'>The current work revealed some special structural elements near the matrix ends of H2 and H3. Presence of a small alanine residue A26 before the conserved kink proline P27 makes the β-turn structure of the [YWF][KR]G motif the only barrier between the solvent in the pocket and the bulk solvent in the matrix side (<a href="#molecules-27-01071-f004" class="html-fig">Figure 4</a>c), and hence the interface between the matrix ends of H2 and H3 is speculated to be more vulnerable upon ligand binding. The vulnerability of this interface was further confirmed by the simulation on the <span class='html-italic'>all4A-AAC</span> mutant (<a href="#molecules-27-01071-f007" class="html-fig">Figure 7</a>d). Residues involved in this interface (A26, T23, W70, R71, G72 and N73) are extremely conserved in both orthologs and paralogs of AAC, SLC25A42, GDC, SCaMC, SLC25A41 and SLC25A43 (<a href="#molecules-27-01071-f004" class="html-fig">Figure 4</a>d). This implies that vulnerability of this interface between domains 1 and 2 could be important for the common transport mechanism of these adenine nucleotide transporters. </div><div class='html-p'>Our previous work showed that due to the dynamic property of H6, the [YWF][KR]G motif in domain 3 lost its β-turn structure in one of the three 3-μs trajectories on <span class='html-italic'>wild-type</span> apo AAC, and Y228 before the kink proline P229 becomes the only barrier to separate the solvent in the pocket from the bulk solvent in the matrix side [<a href="#B17-molecules-27-01071" class="html-bibr">17</a>]. This observation also indicates the vulnerability of the interface between domains 3 and 1. On the other hand, presence of R235 significantly strengthens the H3–H5 (domains 2–3) attachment as mentioned above, and moreover, a stable aromatic cluster forms between the [YWF][RK]G motif and Pro kink region in domain 2 [<a href="#B4-molecules-27-01071" class="html-bibr">4</a>]. These interactions separate the solvent in the pocket far away from the matrix solvent near the interface between domains 2 and 3 (<a href="#app1-molecules-27-01071" class="html-app">Figure S2a</a>). In addition, our previous work also shows that the bound cardiolipin at the specific site of domain 2–3 interface predominantly adopts the inter-domain binding mode [<a href="#B16-molecules-27-01071" class="html-bibr">16</a>]. Therefore, all these simulation results are quite consistent with and also justify the partially asymmetric crystal structure of m-state AAC, in which domains 2 and 3 attach together, while domain 1 separates from the other two domains.</div><div class='html-p'>The transient opening between β-turn structure of the [YWF][KR]G motif of domain 1 and the matrix end of H3 in <span class='html-italic'>all4A-AAC</span> is currently the only structural changes we’ve observed through which solvent in the pocket of AAC can go through to the bulk solvent in the matrix (<a href="#molecules-27-01071-f007" class="html-fig">Figure 7</a>d). A recent study reported that H<sup>+</sup> transport is an integral function of AAC [<a href="#B26-molecules-27-01071" class="html-bibr">26</a>]. We speculate that H<sup>+</sup> could possibly be transported through this transiently opened crevice between the matrix ends of H2 and H3 in c-state AAC even without presence of substrate binding.</div><div class='html-p'>The current work is limited in that the simulation time of 1 μs or 1.5 μs is still too short to sample enough conformational space of AAC. Although the <span class='html-italic'>all3A-AAC</span>, <span class='html-italic'>R235A-AAC</span> and <span class='html-italic'>R279-AAC</span> mutants maintained the crystal structure conformation in the 1-μs simulations, this does not mean that the structure could be stably maintained on longer time scale. Moreover, to observe more drastic conformational changes in the limited simulation time, we used the simplified POPC lipid bilayer without presence of cardiolipins in both wild-type and mutant AAC systems, which may cause some artifacts to the m-gate networks reported here. It will be interesting to elucidate how cardiolipins will affect the m-gate network and structural dynamics of AAC in future studies.</div></section><section id='sec4-molecules-27-01071' type=''><h2 data-nested='1'> 4. Materials and Methods</h2><section id='sec4dot1-molecules-27-01071' type=''><h4 class='html-italic' data-nested='2'> 4.1. System Setup</h4><div class='html-p'>Initial coordinates for the five AAC mutant systems (<span class='html-italic'>all4A-AAC</span>, <span class='html-italic'>all3A-AAC</span>, <span class='html-italic'>R279A-AAC</span>, <span class='html-italic'>R79A-AAC</span>, <span class='html-italic'>R235A-AAC</span>) and the <span class='html-italic'>CATR-AAC</span> complex system were built from the coordinates of the wild-type apo AAC system after the second equilibration step in our previous work [<a href="#B4-molecules-27-01071" class="html-bibr">4</a>]. In the second equilibration step of that work, we used up to 160 ns to fully equilibrate the lipid bilayer and the solvent, with positional restraints applied on heavy atoms of the carrier, and the wild-type AAC system is composed of 70,769 atoms, including one AAC molecule, 219 POPC(palmitoyl-oleoyl-phosphatidylcholine) lipids, 1,2226 water molecules, 23 Na<sup>+</sup> and 42 Cl<sup>-</sup>. Please refer to the work for more details for system setup, energetic minimization and equilibration [<a href="#B4-molecules-27-01071" class="html-bibr">4</a>].</div><div class='html-p'>For the AAC mutants, the non-motif positive residues of AAC were mutated to alanine in PyMOL [<a href="#B27-molecules-27-01071" class="html-bibr">27</a>] (<a href="#molecules-27-01071-t001" class="html-table">Table 1</a>), with the coordinates of lipids and solvent kept from the equilibrated wild-type AAC system, and the reduced positive charges caused by mutations were balanced through removing equal number of sodium ions from the system. To set up the <span class='html-italic'>CATR-AAC</span> system, we fitted the crystal structure of AAC that is bound with CATR (PDB: 1OKC) [<a href="#B8-molecules-27-01071" class="html-bibr">8</a>] to the carrier in the equilibrated system to obtain coordinates of CATR, and we removed the water molecules in the original system that are overlapped with CATR.</div></section><section id='sec4dot2-molecules-27-01071' type=''><h4 class='html-italic' data-nested='2'> 4.2. MD Simulation Protocol</h4><div class='html-p'>MD simulations were carried out with the GROMACS 4.5.5 package [<a href="#B28-molecules-27-01071" class="html-bibr">28</a>] in periodic condition, with the CMAP modified CHARMM36 force field [<a href="#B29-molecules-27-01071" class="html-bibr">29</a>,<a href="#B30-molecules-27-01071" class="html-bibr">30</a>] applied to the protein and the CHARMM lipid parameters used for POPC [<a href="#B31-molecules-27-01071" class="html-bibr">31</a>].After the above systems were setup, each system was first heated from 50 K to 310 K in NBV ensemble with positional restraints applied on all heavy atoms of the protein, and time step was set to 2 fs. In the second and third steps, positional restraints were applied on main-chain atoms and Cα atoms of the protein, respectively, and each step lasts 10 ns. After equilibration, a 1-μs production simulation follows, and for some mutants the simulation was extended to 1.5 μs. The temperature of the system was maintained at 310 K with the v-rescale method [<a href="#B32-molecules-27-01071" class="html-bibr">32</a>], with the coupling time of 0.1 ps. The pressure was maintained at 1 bar using the Berendsen method [<a href="#B33-molecules-27-01071" class="html-bibr">33</a>] with τ<sub>p</sub> of 1.0 ps and compressibility of 4.5 × 10<sup>−5</sup> bar<sup>−1</sup>. The SETTLE [<a href="#B34-molecules-27-01071" class="html-bibr">34</a>] and LINCS constraints [<a href="#B35-molecules-27-01071" class="html-bibr">35</a>] were applied on the hydrogen-involved covalent bonds in water molecules and in other molecules, respectively. Electrostatic interactions were calculated with the Particle-Mesh Ewald (PME) algorithm [<a href="#B36-molecules-27-01071" class="html-bibr">36</a>]. The coordinates of each system were saved every 10 ps. Most analyses were carried out with programs provided in GROMACS package. Trajectories were viewed with VMD [<a href="#B37-molecules-27-01071" class="html-bibr">37</a>], and structural graphics were prepared with PyMOL [<a href="#B27-molecules-27-01071" class="html-bibr">27</a>].</div></section></section><section id='sec5-molecules-27-01071' type='conclusions'><h2 data-nested='1'> 5. Conclusions</h2><div class='html-p'>In the current work, MD simulations on a variety of AAC mutants have demonstrated that: (1) without presence of non-motif positive residues, the charged residues of the PX[DE]XX[KR] motif are prone to form symmetrical inter-helical m-gate network; (2) R235 plays a determinant role in the asymmetry of the m-gate network of AAC; (3) R235 dramatically strengthens the interactions between H3 and H5; (4) R79 promotes intra-helical D231:R234 and weakens inter-helical salt bridges D134:R234 and E29:R137; (5) R279 does not significantly change the profile of the m-gate network. Our simulation results also suggest that the inhibitor CATR promotes symmetrical m-gate network mainly through separating R234 from D231 and fixing R79. Although limited in the length of simulation time, significant changes in the structural dynamics were observed in the <span class='html-italic'>all4A-AAC</span> and <span class='html-italic'>R79A-AAC</span> mutants. The current work highlights that the non-motif positive residues are integral part of the broad m-gate network, and they play different roles in shaping the profile of the broad m-gate network.</div></section> </div> <div class="html-back"> <section><section id='app1-molecules-27-01071' type=''><h2 data-nested='1'> Supplementary Materials</h2><div class='html-p'>The following are available online: Figure S1: The time evolution of the electrostatic interactions within the broad m-gate network in MD simulations on wild-type and mutant AAC. Figure S2: The solvent within the pocket and bulk solvent at the matrix side is more separated due to presence of a tyrosine before the kink proline in domain 2 and domain 3. Figure S3: The R30:R71:R151 stacking structure and time evolution of electrostatic interactions between the capping arginines and N-termini of odd-numbered helices.</div></section></section><section class='html-notes'><h2 >Author Contributions</h2><div class='html-p'>Conceptualization, X.C.; methodology, X.C.; data curation, S.Y., B.M. and Q.Y.; writing—Original draft preparation, S.Y. and B.M.; writing—Review and editing, X.C.; supervision, M.-X.G. and X.C. All authors have read and agreed to the published version of the manuscript.</div></section><section class='html-notes'><h2 >Funding</h2><div class='html-p'>This research was funded by National Natural Science Foundation of China (Grant No. 32171241 to X.C.), Natural Science Foundation of Zhejiang Province (Grant No. LY18C050002 to X.C.).</div></section><section class='html-notes'><h2 >Institutional Review Board Statement</h2><div class='html-p'>Not applicable.</div></section><section class='html-notes'><h2 >Informed Consent Statement</h2><div class='html-p'>Not applicable.</div></section><section class='html-notes'><h2 >Data Availability Statement</h2><div class='html-p'>Data is contained within the article or <a href="#app1-molecules-27-01071" class="html-app">Supplementary Material</a>.</div></section><section id='html-ack' class='html-ack'><h2 >Acknowledgments</h2><div class='html-p'>This work was carried out at National Supercomputer Center in Tianjin, and the calculations were performed on TianHe-1(A).</div></section><section class='html-notes'><h2 >Conflicts of Interest</h2><div class='html-p'>The authors declare no conflict of interest.</div></section><section class='html-notes'><h2 >Sample Availability</h2><div class='html-p'>Samples are not available from the authors.</div></section><section id='html-glossary'><h2 >Abbreviations</h2><table class='html-array_table'><tbody ><tr ><td align='left' valign='middle' class='html-align-left' >AAC</td><td align='left' valign='middle' class='html-align-left' >ADP/ATP carrier</td></tr><tr ><td align='left' valign='middle' class='html-align-left' >ATR</td><td align='left' valign='middle' class='html-align-left' >atractyloside</td></tr><tr ><td align='left' valign='middle' class='html-align-left' >BKA</td><td align='left' valign='middle' class='html-align-left' >bongkrekic acid</td></tr><tr ><td align='left' valign='middle' class='html-align-left' >CATR</td><td align='left' valign='middle' class='html-align-left' >carboxyatractyloside</td></tr><tr ><td align='left' valign='middle' class='html-align-left' >GDC</td><td align='left' valign='middle' class='html-align-left' >graves disease carrier</td></tr><tr ><td align='left' valign='middle' class='html-align-left' >hAAC1</td><td align='left' valign='middle' class='html-align-left' >human ADP/ATP carrier 1</td></tr><tr ><td align='left' valign='middle' class='html-align-left' >IMM</td><td align='left' valign='middle' class='html-align-left' >the inner mitochondrial membrane</td></tr><tr ><td align='left' valign='middle' class='html-align-left' >m-gate</td><td align='left' valign='middle' class='html-align-left' >matrix gate</td></tr><tr ><td align='left' valign='middle' class='html-align-left' >MCF</td><td align='left' valign='middle' class='html-align-left' >mitochondrial carrier family</td></tr><tr ><td align='left' valign='middle' class='html-align-left' >MCs</td><td align='left' valign='middle' class='html-align-left' >mitochondrial carriers</td></tr><tr ><td align='left' valign='middle' class='html-align-left' >MD</td><td align='left' valign='middle' class='html-align-left' >molecular dynamics</td></tr><tr ><td align='left' valign='middle' class='html-align-left' >OXPHOS</td><td align='left' valign='middle' class='html-align-left' >oxidative phosphorylation</td></tr><tr ><td align='left' valign='middle' class='html-align-left' >POPC</td><td align='left' valign='middle' class='html-align-left' >palmitoyl-oleoyl-phosphatidylcholine</td></tr><tr ><td align='left' valign='middle' class='html-align-left' >RMSF</td><td align='left' valign='middle' class='html-align-left' >root-mean square fluctuation</td></tr><tr ><td align='left' valign='middle' class='html-align-left' >SCaMC</td><td align='left' valign='middle' class='html-align-left' >calcium-binding mitochondrial carrier protein</td></tr><tr ><td align='left' valign='middle' class='html-align-left' >SLC</td><td align='left' valign='middle' class='html-align-left' >solute carrier</td></tr><tr ><td align='left' valign='middle' class='html-align-left' >SLC25A16</td><td align='left' valign='middle' class='html-align-left' >Solute carrier family 25, member 16</td></tr></tbody></table></section><section id='html-references_list'><h2>References</h2><ol class='html-xx'><li id='B1-molecules-27-01071' class='html-x' data-content='1.'>Aquila, H.; Link, T.A.; Klingenberg, M. Solute carriers involved in energy transfer of mitochondria form a homologous protein family. <span class='html-italic'>FEBS Lett.</span> <b>1987</b>, <span class='html-italic'>212</span>, 1–9. [<a href="https://scholar.google.com/scholar_lookup?title=Solute+carriers+involved+in+energy+transfer+of+mitochondria+form+a+homologous+protein+family&author=Aquila,+H.&author=Link,+T.A.&author=Klingenberg,+M.&publication_year=1987&journal=FEBS+Lett.&volume=212&pages=1%E2%80%939&doi=10.1016/0014-5793(87)81546-6" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1016/0014-5793(87)81546-6" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>] [<a href="" target='_blank' rel="noopener noreferrer">Green Version</a>]</li><li id='B2-molecules-27-01071' class='html-x' data-content='2.'>Palmieri, F. Mitochondrial carrier proteins. <span class='html-italic'>FEBS Lett.</span> <b>1994</b>, <span class='html-italic'>346</span>, 48–54. [<a href="https://scholar.google.com/scholar_lookup?title=Mitochondrial+carrier+proteins&author=Palmieri,+F.&publication_year=1994&journal=FEBS+Lett.&volume=346&pages=48%E2%80%9354&doi=10.1016/0014-5793(94)00329-7" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1016/0014-5793(94)00329-7" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>] [<a href="" target='_blank' rel="noopener noreferrer">Green Version</a>]</li><li id='B3-molecules-27-01071' class='html-x' data-content='3.'>Ruprecht, J.J.; Kunji, E.R.S. Structural Mechanism of Transport of Mitochondrial Carriers. <span class='html-italic'>Annu. Rev. Biochem.</span> <b>2021</b>, <span class='html-italic'>90</span>, 535–558. [<a href="https://scholar.google.com/scholar_lookup?title=Structural+Mechanism+of+Transport+of+Mitochondrial+Carriers&author=Ruprecht,+J.J.&author=Kunji,+E.R.S.&publication_year=2021&journal=Annu.+Rev.+Biochem.&volume=90&pages=535%E2%80%93558&doi=10.1146/annurev-biochem-072820-020508&pmid=33556281" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1146/annurev-biochem-072820-020508" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>] [<a href="http://www.ncbi.nlm.nih.gov/pubmed/33556281" class='cross-ref' data-typ='pmid' target='_blank' rel='noopener noreferrer'>PubMed</a>]</li><li id='B4-molecules-27-01071' class='html-x' data-content='4.'>Yi, Q.; Li, Q.; Yao, S.; Chen, Y.; Guan, M.X.; Cang, X. Molecular dynamics simulations on apo ADP/ATP carrier shed new lights on the featured motif of the mitochondrial carriers. <span class='html-italic'>Mitochondrion</span> <b>2019</b>, <span class='html-italic'>47</span>, 94–102. [<a href="https://scholar.google.com/scholar_lookup?title=Molecular+dynamics+simulations+on+apo+ADP/ATP+carrier+shed+new+lights+on+the+featured+motif+of+the+mitochondrial+carriers&author=Yi,+Q.&author=Li,+Q.&author=Yao,+S.&author=Chen,+Y.&author=Guan,+M.X.&author=Cang,+X.&publication_year=2019&journal=Mitochondrion&volume=47&pages=94%E2%80%93102&doi=10.1016/j.mito.2019.05.006" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1016/j.mito.2019.05.006" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>]</li><li id='B5-molecules-27-01071' class='html-x' data-content='5.'>Robinson, A.J.; Overy, C.; Kunji, E.R. The mechanism of transport by mitochondrial carriers based on analysis of symmetry. <span class='html-italic'>Proc. Natl. Acad. Sci. USA</span> <b>2008</b>, <span class='html-italic'>105</span>, 17766–17771. [<a href="https://scholar.google.com/scholar_lookup?title=The+mechanism+of+transport+by+mitochondrial+carriers+based+on+analysis+of+symmetry&author=Robinson,+A.J.&author=Overy,+C.&author=Kunji,+E.R.&publication_year=2008&journal=Proc.+Natl.+Acad.+Sci.+USA&volume=105&pages=17766%E2%80%9317771&doi=10.1073/pnas.0809580105" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1073/pnas.0809580105" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>] [<a href="http://www.pnas.org/content/105/46/17766.full.pdf" target='_blank' rel="noopener noreferrer">Green Version</a>]</li><li id='B6-molecules-27-01071' class='html-x' data-content='6.'>Pierri, C.L.; Palmieri, F.; De Grassi, A. Single-nucleotide evolution quantifies the importance of each site along the structure of mitochondrial carriers. <span class='html-italic'>Cell. Mol. Life Sci.</span> <b>2014</b>, <span class='html-italic'>71</span>, 349–364. [<a href="https://scholar.google.com/scholar_lookup?title=Single-nucleotide+evolution+quantifies+the+importance+of+each+site+along+the+structure+of+mitochondrial+carriers&author=Pierri,+C.L.&author=Palmieri,+F.&author=De+Grassi,+A.&publication_year=2014&journal=Cell.+Mol.+Life+Sci.&volume=71&pages=349%E2%80%93364&doi=10.1007/s00018-013-1389-y" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1007/s00018-013-1389-y" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>]</li><li id='B7-molecules-27-01071' class='html-x' data-content='7.'>Klingenberg, M. The ADP and ATP transport in mitochondria and its carrier. <span class='html-italic'>Biochim. Biophys. Acta</span> <b>2008</b>, <span class='html-italic'>1778</span>, 1978–2021. [<a href="https://scholar.google.com/scholar_lookup?title=The+ADP+and+ATP+transport+in+mitochondria+and+its+carrier&author=Klingenberg,+M.&publication_year=2008&journal=Biochim.+Biophys.+Acta&volume=1778&pages=1978%E2%80%932021&doi=10.1016/j.bbamem.2008.04.011" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1016/j.bbamem.2008.04.011" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>] [<a href="" target='_blank' rel="noopener noreferrer">Green Version</a>]</li><li id='B8-molecules-27-01071' class='html-x' data-content='8.'>Pebay-Peyroula, E.; Dahout-Gonzalez, C.; Kahn, R.; Trezeguet, V.; Lauquin, G.J.; Brandolin, G. Structure of mitochondrial ADP/ATP carrier in complex with carboxyatractyloside. <span class='html-italic'>Nature</span> <b>2003</b>, <span class='html-italic'>426</span>, 39–44. [<a href="https://scholar.google.com/scholar_lookup?title=Structure+of+mitochondrial+ADP/ATP+carrier+in+complex+with+carboxyatractyloside&author=Pebay-Peyroula,+E.&author=Dahout-Gonzalez,+C.&author=Kahn,+R.&author=Trezeguet,+V.&author=Lauquin,+G.J.&author=Brandolin,+G.&publication_year=2003&journal=Nature&volume=426&pages=39%E2%80%9344&doi=10.1038/nature02056" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1038/nature02056" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>]</li><li id='B9-molecules-27-01071' class='html-x' data-content='9.'>Ruprecht, J.J.; Hellawell, A.M.; Harding, M.; Crichton, P.G.; McCoy, A.J.; Kunji, E.R. Structures of yeast mitochondrial ADP/ATP carriers support a domain-based alternating-access transport mechanism. <span class='html-italic'>Proc. Natl. Acad. Sci. USA</span> <b>2014</b>, <span class='html-italic'>111</span>, E426–E434. [<a href="https://scholar.google.com/scholar_lookup?title=Structures+of+yeast+mitochondrial+ADP/ATP+carriers+support+a+domain-based+alternating-access+transport+mechanism&author=Ruprecht,+J.J.&author=Hellawell,+A.M.&author=Harding,+M.&author=Crichton,+P.G.&author=McCoy,+A.J.&author=Kunji,+E.R.&publication_year=2014&journal=Proc.+Natl.+Acad.+Sci.+USA&volume=111&pages=E426%E2%80%93E434&doi=10.1073/pnas.1320692111" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1073/pnas.1320692111" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>] [<a href="https://www.pnas.org/content/pnas/111/4/E426.full.pdf" target='_blank' rel="noopener noreferrer">Green Version</a>]</li><li id='B10-molecules-27-01071' class='html-xx' data-content='10.'>Palmieri, F.; Pierri, C.L. Structure and function of mitochondrial carriers—Role of the transmembrane helix P and G residues in the gating and transport mechanism. <span class='html-italic'>FEBS Lett.</span> <b>2010</b>, <span class='html-italic'>584</span>, 1931–1939. [<a href="https://scholar.google.com/scholar_lookup?title=Structure+and+function+of+mitochondrial+carriers%E2%80%94Role+of+the+transmembrane+helix+P+and+G+residues+in+the+gating+and+transport+mechanism&author=Palmieri,+F.&author=Pierri,+C.L.&publication_year=2010&journal=FEBS+Lett.&volume=584&pages=1931%E2%80%931939&doi=10.1016/j.febslet.2009.10.063" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1016/j.febslet.2009.10.063" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>] [<a href="" target='_blank' rel="noopener noreferrer">Green Version</a>]</li><li id='B11-molecules-27-01071' class='html-xx' data-content='11.'>Kunji, E.R.; Robinson, A.J. Coupling of proton and substrate translocation in the transport cycle of mitochondrial carriers. <span class='html-italic'>Curr. Opin. Struct. Biol.</span> <b>2010</b>, <span class='html-italic'>20</span>, 440–447. [<a href="https://scholar.google.com/scholar_lookup?title=Coupling+of+proton+and+substrate+translocation+in+the+transport+cycle+of+mitochondrial+carriers&author=Kunji,+E.R.&author=Robinson,+A.J.&publication_year=2010&journal=Curr.+Opin.+Struct.+Biol.&volume=20&pages=440%E2%80%93447&doi=10.1016/j.sbi.2010.06.004&pmid=20598524" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1016/j.sbi.2010.06.004" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>] [<a href="http://www.ncbi.nlm.nih.gov/pubmed/20598524" class='cross-ref' data-typ='pmid' target='_blank' rel='noopener noreferrer'>PubMed</a>]</li><li id='B12-molecules-27-01071' class='html-xx' data-content='12.'>Wang, Y.; Tajkhorshid, E. Electrostatic funneling of substrate in mitochondrial inner membrane carriers. <span class='html-italic'>Proc. Natl. Acad. Sci. USA</span> <b>2008</b>, <span class='html-italic'>105</span>, 9598–9603. [<a href="https://scholar.google.com/scholar_lookup?title=Electrostatic+funneling+of+substrate+in+mitochondrial+inner+membrane+carriers&author=Wang,+Y.&author=Tajkhorshid,+E.&publication_year=2008&journal=Proc.+Natl.+Acad.+Sci.+USA&volume=105&pages=9598%E2%80%939603&doi=10.1073/pnas.0801786105&pmid=18621725" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1073/pnas.0801786105" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>] [<a href="http://www.ncbi.nlm.nih.gov/pubmed/18621725" class='cross-ref' data-typ='pmid' target='_blank' rel='noopener noreferrer'>PubMed</a>] [<a href="http://www.pnas.org/content/105/28/9598.full.pdf" target='_blank' rel="noopener noreferrer">Green Version</a>]</li><li id='B13-molecules-27-01071' class='html-xx' data-content='13.'>Johnston, J.M.; Khalid, S.; Sansom, M.S. Conformational dynamics of the mitochondrial ADP/ATP carrier: A simulation study. <span class='html-italic'>Mol. Membr. Biol.</span> <b>2008</b>, <span class='html-italic'>25</span>, 506–517. [<a href="https://scholar.google.com/scholar_lookup?title=Conformational+dynamics+of+the+mitochondrial+ADP/ATP+carrier:+A+simulation+study&author=Johnston,+J.M.&author=Khalid,+S.&author=Sansom,+M.S.&publication_year=2008&journal=Mol.+Membr.+Biol.&volume=25&pages=506%E2%80%93517&doi=10.1080/09687680802459271&pmid=18988066" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1080/09687680802459271" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>] [<a href="http://www.ncbi.nlm.nih.gov/pubmed/18988066" class='cross-ref' data-typ='pmid' target='_blank' rel='noopener noreferrer'>PubMed</a>]</li><li id='B14-molecules-27-01071' class='html-xx' data-content='14.'>Dehez, F.; Pebay-Peyroula, E.; Chipot, C. Binding of ADP in the mitochondrial ADP/ATP carrier is driven by an electrostatic funnel. <span class='html-italic'>J. Am. Chem. Soc.</span> <b>2008</b>, <span class='html-italic'>130</span>, 12725–12733. [<a href="https://scholar.google.com/scholar_lookup?title=Binding+of+ADP+in+the+mitochondrial+ADP/ATP+carrier+is+driven+by+an+electrostatic+funnel&author=Dehez,+F.&author=Pebay-Peyroula,+E.&author=Chipot,+C.&publication_year=2008&journal=J.+Am.+Chem.+Soc.&volume=130&pages=12725%E2%80%9312733&doi=10.1021/ja8033087&pmid=18729359" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1021/ja8033087" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>] [<a href="http://www.ncbi.nlm.nih.gov/pubmed/18729359" class='cross-ref' data-typ='pmid' target='_blank' rel='noopener noreferrer'>PubMed</a>]</li><li id='B15-molecules-27-01071' class='html-xx' data-content='15.'>Ruprecht, J.J.; King, M.S.; Zogg, T.; Aleksandrova, A.A.; Pardon, E.; Crichton, P.G.; Steyaert, J.; Kunji, E.R.S. The Molecular Mechanism of Transport by the Mitochondrial ADP/ATP Carrier. <span class='html-italic'>Cell</span> <b>2019</b>, <span class='html-italic'>176</span>, 435–447. [<a href="https://scholar.google.com/scholar_lookup?title=The+Molecular+Mechanism+of+Transport+by+the+Mitochondrial+ADP/ATP+Carrier&author=Ruprecht,+J.J.&author=King,+M.S.&author=Zogg,+T.&author=Aleksandrova,+A.A.&author=Pardon,+E.&author=Crichton,+P.G.&author=Steyaert,+J.&author=Kunji,+E.R.S.&publication_year=2019&journal=Cell&volume=176&pages=435%E2%80%93447&doi=10.1016/j.cell.2018.11.025" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1016/j.cell.2018.11.025" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>] [<a href="http://www.cell.com/article/S0092867418315174/pdf" target='_blank' rel="noopener noreferrer">Green Version</a>]</li><li id='B16-molecules-27-01071' class='html-xx' data-content='16.'>Mao, X.; Yao, S.; Yi, Q.; Xu, Z.M.; Cang, X. Function-related asymmetry of the specific cardiolipin binding sites on the mitochondrial ADP/ATP carrier. <span class='html-italic'>Biochim. Biophys. Acta Biomembr.</span> <b>2021</b>, <span class='html-italic'>1863</span>, 183466. [<a href="https://scholar.google.com/scholar_lookup?title=Function-related+asymmetry+of+the+specific+cardiolipin+binding+sites+on+the+mitochondrial+ADP/ATP+carrier&author=Mao,+X.&author=Yao,+S.&author=Yi,+Q.&author=Xu,+Z.M.&author=Cang,+X.&publication_year=2021&journal=Biochim.+Biophys.+Acta+Biomembr.&volume=1863&pages=183466&doi=10.1016/j.bbamem.2020.183466" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1016/j.bbamem.2020.183466" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>]</li><li id='B17-molecules-27-01071' class='html-xx' data-content='17.'>Yao, S.; Yi, Q.; Ma, B.; Mao, X.; Chen, Y.; Guan, M.-X.; Cang, X. Structural Basis of Substrate Recognition by the Mitochondrial ADP/ATP Transporter. <span class='html-italic'>BioRxiv</span> <b>2021</b>, preprint. [<a href="https://scholar.google.com/scholar_lookup?title=Structural+Basis+of+Substrate+Recognition+by+the+Mitochondrial+ADP/ATP+Transporter&author=Yao,+S.&author=Yi,+Q.&author=Ma,+B.&author=Mao,+X.&author=Chen,+Y.&author=Guan,+M.-X.&author=Cang,+X.&publication_year=2021&journal=BioRxiv&pages=preprint&doi=10.1101/2021.09.15.460093" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1101/2021.09.15.460093" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>]</li><li id='B18-molecules-27-01071' class='html-xx' data-content='18.'>Montalvo-Acosta, J.J.; Kunji, E.R.S.; Ruprecht, J.J.; Dehez, F.; Chipot, C. Structure, substrate binding, and symmetry of the mitochondrial ADP/ATP carrier in its matrix-open state. <span class='html-italic'>Biophys. J.</span> <b>2021</b>, <span class='html-italic'>120</span>, 5187–5195. [<a href="https://scholar.google.com/scholar_lookup?title=Structure,+substrate+binding,+and+symmetry+of+the+mitochondrial+ADP/ATP+carrier+in+its+matrix-open+state&author=Montalvo-Acosta,+J.J.&author=Kunji,+E.R.S.&author=Ruprecht,+J.J.&author=Dehez,+F.&author=Chipot,+C.&publication_year=2021&journal=Biophys.+J.&volume=120&pages=5187%E2%80%935195&doi=10.1016/j.bpj.2021.11.002" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1016/j.bpj.2021.11.002" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>]</li><li id='B19-molecules-27-01071' class='html-xx' data-content='19.'>Falconi, M.; Chillemi, G.; Di Marino, D.; D’Annessa, I.; Morozzo della Rocca, B.; Palmieri, L.; Desideri, A. Structural dynamics of the mitochondrial ADP/ATP carrier revealed by molecular dynamics simulation studies. <span class='html-italic'>Proteins</span> <b>2006</b>, <span class='html-italic'>65</span>, 681–691. [<a href="https://scholar.google.com/scholar_lookup?title=Structural+dynamics+of+the+mitochondrial+ADP/ATP+carrier+revealed+by+molecular+dynamics+simulation+studies&author=Falconi,+M.&author=Chillemi,+G.&author=Di+Marino,+D.&author=D%E2%80%99Annessa,+I.&author=Morozzo+della+Rocca,+B.&author=Palmieri,+L.&author=Desideri,+A.&publication_year=2006&journal=Proteins&volume=65&pages=681%E2%80%93691&doi=10.1002/prot.21102" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1002/prot.21102" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>]</li><li id='B20-molecules-27-01071' class='html-xx' data-content='20.'>Ardalan, A.; Sowlati-Hashjin, S.; Oduwoye, H.; Uwumarenogie, S.O.; Karttunen, M.; Smith, M.D.; Jelokhani-Niaraki, M. Biphasic Proton Transport Mechanism for Uncoupling Proteins. <span class='html-italic'>J. Phys. Chem.</span> <b>2021</b>, <span class='html-italic'>125</span>, 9130–9144. [<a href="https://scholar.google.com/scholar_lookup?title=Biphasic+Proton+Transport+Mechanism+for+Uncoupling+Proteins&author=Ardalan,+A.&author=Sowlati-Hashjin,+S.&author=Oduwoye,+H.&author=Uwumarenogie,+S.O.&author=Karttunen,+M.&author=Smith,+M.D.&author=Jelokhani-Niaraki,+M.&publication_year=2021&journal=J.+Phys.+Chem.&volume=125&pages=9130%E2%80%939144&doi=10.1021/acs.jpcb.1c04766" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1021/acs.jpcb.1c04766" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>]</li><li id='B21-molecules-27-01071' class='html-xx' data-content='21.'>Nelson, D.R.; Lawson, J.E.; Klingenberg, M.; Douglas, M.G. Site-directed mutagenesis of the yeast mitochondrial ADP/ATP translocator. Six arginines and one lysine are essential. <span class='html-italic'>J. Mol. Biol.</span> <b>1993</b>, <span class='html-italic'>230</span>, 1159–1170. [<a href="https://scholar.google.com/scholar_lookup?title=Site-directed+mutagenesis+of+the+yeast+mitochondrial+ADP/ATP+translocator.+Six+arginines+and+one+lysine+are+essential&author=Nelson,+D.R.&author=Lawson,+J.E.&author=Klingenberg,+M.&author=Douglas,+M.G.&publication_year=1993&journal=J.+Mol.+Biol.&volume=230&pages=1159%E2%80%931170&doi=10.1006/jmbi.1993.1233&pmid=8487299" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1006/jmbi.1993.1233" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>] [<a href="http://www.ncbi.nlm.nih.gov/pubmed/8487299" class='cross-ref' data-typ='pmid' target='_blank' rel='noopener noreferrer'>PubMed</a>]</li><li id='B22-molecules-27-01071' class='html-xx' data-content='22.'>Muller, V.; Basset, G.; Nelson, D.R.; Klingenberg, M. Probing the role of positive residues in the ADP/ATP carrier from yeast. The effect of six arginine mutations of oxidative phosphorylation and AAC expression. <span class='html-italic'>Biochemistry</span> <b>1996</b>, <span class='html-italic'>35</span>, 16132–16143. [<a href="https://scholar.google.com/scholar_lookup?title=Probing+the+role+of+positive+residues+in+the+ADP/ATP+carrier+from+yeast.+The+effect+of+six+arginine+mutations+of+oxidative+phosphorylation+and+AAC+expression&author=Muller,+V.&author=Basset,+G.&author=Nelson,+D.R.&author=Klingenberg,+M.&publication_year=1996&journal=Biochemistry&volume=35&pages=16132%E2%80%9316143&doi=10.1021/bi960667r&pmid=8973185" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1021/bi960667r" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>] [<a href="http://www.ncbi.nlm.nih.gov/pubmed/8973185" class='cross-ref' data-typ='pmid' target='_blank' rel='noopener noreferrer'>PubMed</a>]</li><li id='B23-molecules-27-01071' class='html-xx' data-content='23.'>Thompson, K.; Majd, H.; Dallabona, C.; Reinson, K.; King, M.S.; Alston, C.L.; He, L.; Lodi, T.; Jones, S.A.; Fattal-Valevski, A.; et al. Recurrent De Novo Dominant Mutations in SLC25A4 Cause Severe Early-Onset Mitochondrial Disease and Loss of Mitochondrial DNA Copy Number. <span class='html-italic'>Am. J. Hum. Genet.</span> <b>2016</b>, <span class='html-italic'>99</span>, 1405. [<a href="https://scholar.google.com/scholar_lookup?title=Recurrent+De+Novo+Dominant+Mutations+in+SLC25A4+Cause+Severe+Early-Onset+Mitochondrial+Disease+and+Loss+of+Mitochondrial+DNA+Copy+Number&author=Thompson,+K.&author=Majd,+H.&author=Dallabona,+C.&author=Reinson,+K.&author=King,+M.S.&author=Alston,+C.L.&author=He,+L.&author=Lodi,+T.&author=Jones,+S.A.&author=Fattal-Valevski,+A.&publication_year=2016&journal=Am.+J.+Hum.+Genet.&volume=99&pages=1405&doi=10.1016/j.ajhg.2016.11.001" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.11.001" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>]</li><li id='B24-molecules-27-01071' class='html-xx' data-content='24.'>Mielke, C.; Lefort, N.; McLean, C.G.; Cordova, J.M.; Langlais, P.R.; Bordner, A.J.; Te, J.A.; Ozkan, S.B.; Willis, W.T.; Mandarino, L.J. Adenine Nucleotide Translocase Is Acetylated in Vivo in Human Muscle: Modeling Predicts a Decreased ADP Affinity and Altered Control of Oxidative Phosphorylation. <span class='html-italic'>Biochemistry</span> <b>2014</b>, <span class='html-italic'>53</span>, 3817–3829. [<a href="https://scholar.google.com/scholar_lookup?title=Adenine+Nucleotide+Translocase+Is+Acetylated+in+Vivo+in+Human+Muscle:+Modeling+Predicts+a+Decreased+ADP+Affinity+and+Altered+Control+of+Oxidative+Phosphorylation&author=Mielke,+C.&author=Lefort,+N.&author=McLean,+C.G.&author=Cordova,+J.M.&author=Langlais,+P.R.&author=Bordner,+A.J.&author=Te,+J.A.&author=Ozkan,+S.B.&author=Willis,+W.T.&author=Mandarino,+L.J.&publication_year=2014&journal=Biochemistry&volume=53&pages=3817%E2%80%933829&doi=10.1021/bi401651e" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1021/bi401651e" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>] [<a href="https://pubs.acs.org/doi/pdf/10.1021/bi401651e" target='_blank' rel="noopener noreferrer">Green Version</a>]</li><li id='B25-molecules-27-01071' class='html-xx' data-content='25.'>Finlayson, J.; Barakati, N.; Langlais, P.R.; Funk, J.; Zapata Bustos, R.; Coletta, D.K.; Luo, M.; Willis, W.T.; Mandarino, L.J. Site-specific acetylation of adenine nucleotide translocase 1 at lysine 23 in human muscle. <span class='html-italic'>Anal. Biochem.</span> <b>2021</b>, <span class='html-italic'>630</span>, 114319. [<a href="https://scholar.google.com/scholar_lookup?title=Site-specific+acetylation+of+adenine+nucleotide+translocase+1+at+lysine+23+in+human+muscle&author=Finlayson,+J.&author=Barakati,+N.&author=Langlais,+P.R.&author=Funk,+J.&author=Zapata+Bustos,+R.&author=Coletta,+D.K.&author=Luo,+M.&author=Willis,+W.T.&author=Mandarino,+L.J.&publication_year=2021&journal=Anal.+Biochem.&volume=630&pages=114319&doi=10.1016/j.ab.2021.114319&pmid=34332952" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1016/j.ab.2021.114319" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>] [<a href="http://www.ncbi.nlm.nih.gov/pubmed/34332952" class='cross-ref' data-typ='pmid' target='_blank' rel='noopener noreferrer'>PubMed</a>]</li><li id='B26-molecules-27-01071' class='html-xx' data-content='26.'>Bertholet, A.M.; Chouchani, E.T.; Kazak, L.; Angelin, A.; Fedorenko, A.; Long, J.Z.; Vidoni, S.; Garrity, R.; Cho, J.; Terada, N.; et al. H(+) transport is an integral function of the mitochondrial ADP/ATP carrier. <span class='html-italic'>Nature</span> <b>2019</b>, <span class='html-italic'>571</span>, 515–520. [<a href="https://scholar.google.com/scholar_lookup?title=H(+)+transport+is+an+integral+function+of+the+mitochondrial+ADP/ATP+carrier&author=Bertholet,+A.M.&author=Chouchani,+E.T.&author=Kazak,+L.&author=Angelin,+A.&author=Fedorenko,+A.&author=Long,+J.Z.&author=Vidoni,+S.&author=Garrity,+R.&author=Cho,+J.&author=Terada,+N.&publication_year=2019&journal=Nature&volume=571&pages=515%E2%80%93520&doi=10.1038/s41586-019-1400-3&pmid=31341297" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1038/s41586-019-1400-3" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>] [<a href="http://www.ncbi.nlm.nih.gov/pubmed/31341297" class='cross-ref' data-typ='pmid' target='_blank' rel='noopener noreferrer'>PubMed</a>]</li><li id='B27-molecules-27-01071' class='html-xx' data-content='27.'>Delano, W. Pymol Molecular Graphics System: An open-source molecular graphics tool. <span class='html-italic'>CCP4 Newsl. Protein Crystallogr.</span> <b>2002</b>, <span class='html-italic'>40</span>, 82–92. [<a href="https://scholar.google.com/scholar_lookup?title=Pymol+Molecular+Graphics+System:+An+open-source+molecular+graphics+tool&author=Delano,+W.&publication_year=2002&journal=CCP4+Newsl.+Protein+Crystallogr.&volume=40&pages=82%E2%80%9392" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>]</li><li id='B28-molecules-27-01071' class='html-xx' data-content='28.'>Hess, B.; Kutzner, C.; van der Spoel, D.; Lindahl, E. GROMACS 4: Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation. <span class='html-italic'>J. Chem. Theory Comput.</span> <b>2008</b>, <span class='html-italic'>4</span>, 435–447. [<a href="https://scholar.google.com/scholar_lookup?title=GROMACS+4:+Algorithms+for+Highly+Efficient,+Load-Balanced,+and+Scalable+Molecular+Simulation&author=Hess,+B.&author=Kutzner,+C.&author=van+der+Spoel,+D.&author=Lindahl,+E.&publication_year=2008&journal=J.+Chem.+Theory+Comput.&volume=4&pages=435%E2%80%93447&doi=10.1021/ct700301q" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1021/ct700301q" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>] [<a href="https://pure.mpg.de/pubman/item/item_588952_3/component/file_588951/412029.pdf" target='_blank' rel="noopener noreferrer">Green Version</a>]</li><li id='B29-molecules-27-01071' class='html-xx' data-content='29.'>Huang, J.; MacKerell, A.D., Jr. CHARMM36 all-atom additive protein force field: Validation based on comparison to NMR data. <span class='html-italic'>J. Comput. Chem.</span> <b>2013</b>, <span class='html-italic'>34</span>, 2135–2145. [<a href="https://scholar.google.com/scholar_lookup?title=CHARMM36+all-atom+additive+protein+force+field:+Validation+based+on+comparison+to+NMR+data&author=Huang,+J.&author=MacKerell,+A.D.,+Jr.&publication_year=2013&journal=J.+Comput.+Chem.&volume=34&pages=2135%E2%80%932145&doi=10.1002/jcc.23354" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1002/jcc.23354" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>] [<a href="http://europepmc.org/articles/pmc3800559?pdf=render" target='_blank' rel="noopener noreferrer">Green Version</a>]</li><li id='B30-molecules-27-01071' class='html-xx' data-content='30.'>MacKerell, A., Jr.; Feig, M.; Rd, B.C. Extending the treatment of backbone energetics in protein force fields: Limitations of gas-phase quantum mechanics in reproducing protein conformational distributions in molecular dynamics simulations. <span class='html-italic'>J. Comput. Chem.</span> <b>2004</b>, <span class='html-italic'>25</span>, 1400–1415. [<a href="https://scholar.google.com/scholar_lookup?title=Extending+the+treatment+of+backbone+energetics+in+protein+force+fields:+Limitations+of+gas-phase+quantum+mechanics+in+reproducing+protein+conformational+distributions+in+molecular+dynamics+simulations&author=MacKerell,+A.,+Jr.&author=Feig,+M.&author=Rd,+B.C.&publication_year=2004&journal=J.+Comput.+Chem.&volume=25&pages=1400%E2%80%931415&doi=10.1002/jcc.20065" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1002/jcc.20065" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>]</li><li id='B31-molecules-27-01071' class='html-xx' data-content='31.'>Klauda, J.B.; Venable, R.M.; Freites, J.A.; O’Connor, J.W.; Tobias, D.J.; Mondragon-Ramirez, C.; Vorobyov, I.; MacKerell, A.D., Jr.; Pastor, R.W. Update of the CHARMM all-atom additive force field for lipids: Validation on six lipid types. <span class='html-italic'>J. Phys. Chem.</span> <b>2010</b>, <span class='html-italic'>114</span>, 7830–7843. [<a href="https://scholar.google.com/scholar_lookup?title=Update+of+the+CHARMM+all-atom+additive+force+field+for+lipids:+Validation+on+six+lipid+types&author=Klauda,+J.B.&author=Venable,+R.M.&author=Freites,+J.A.&author=O%E2%80%99Connor,+J.W.&author=Tobias,+D.J.&author=Mondragon-Ramirez,+C.&author=Vorobyov,+I.&author=MacKerell,+A.D.,+Jr.&author=Pastor,+R.W.&publication_year=2010&journal=J.+Phys.+Chem.&volume=114&pages=7830%E2%80%937843&doi=10.1021/jp101759q&pmid=20496934" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1021/jp101759q" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>] [<a href="http://www.ncbi.nlm.nih.gov/pubmed/20496934" class='cross-ref' data-typ='pmid' target='_blank' rel='noopener noreferrer'>PubMed</a>] [<a href="http://europepmc.org/articles/pmc2922408?pdf=render" target='_blank' rel="noopener noreferrer">Green Version</a>]</li><li id='B32-molecules-27-01071' class='html-xx' data-content='32.'>Bussi, G.; Donadio, D.; Parrinello, M. Canonical sampling through velocity rescaling. <span class='html-italic'>J. Chem. Phys.</span> <b>2007</b>, <span class='html-italic'>126</span>, 2384. [<a href="https://scholar.google.com/scholar_lookup?title=Canonical+sampling+through+velocity+rescaling&author=Bussi,+G.&author=Donadio,+D.&author=Parrinello,+M.&publication_year=2007&journal=J.+Chem.+Phys.&volume=126&pages=2384&doi=10.1063/1.2408420&pmid=17212484" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1063/1.2408420" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>] [<a href="http://www.ncbi.nlm.nih.gov/pubmed/17212484" class='cross-ref' data-typ='pmid' target='_blank' rel='noopener noreferrer'>PubMed</a>] [<a href="http://arxiv.org/pdf/0803.4060" target='_blank' rel="noopener noreferrer">Green Version</a>]</li><li id='B33-molecules-27-01071' class='html-xx' data-content='33.'>Berendsen, H.J.C.; Postma, J.P.M.; Vangunsteren, W.F.; Dinola, A.; Haak, J.R. Molecular-Dynamics with Coupling To an External Bath. <span class='html-italic'>J. Chem. Phys.</span> <b>1984</b>, <span class='html-italic'>81</span>, 3684–3690. [<a href="https://scholar.google.com/scholar_lookup?title=Molecular-Dynamics+with+Coupling+To+an+External+Bath&author=Berendsen,+H.J.C.&author=Postma,+J.P.M.&author=Vangunsteren,+W.F.&author=Dinola,+A.&author=Haak,+J.R.&publication_year=1984&journal=J.+Chem.+Phys.&volume=81&pages=3684%E2%80%933690&doi=10.1063/1.448118" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1063/1.448118" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>] [<a href="https://pure.rug.nl/ws/files/64380902/1.448118.pdf" target='_blank' rel="noopener noreferrer">Green Version</a>]</li><li id='B34-molecules-27-01071' class='html-xx' data-content='34.'>Miyamoto, S.; Kollman, P.A. Settle—An Analytical Version of the Shake and Rattle Algorithm for Rigid Water Models. <span class='html-italic'>J. Comput. Chem.</span> <b>1992</b>, <span class='html-italic'>13</span>, 952–962. [<a href="https://scholar.google.com/scholar_lookup?title=Settle%E2%80%94An+Analytical+Version+of+the+Shake+and+Rattle+Algorithm+for+Rigid+Water+Models&author=Miyamoto,+S.&author=Kollman,+P.A.&publication_year=1992&journal=J.+Comput.+Chem.&volume=13&pages=952%E2%80%93962&doi=10.1002/jcc.540130805" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1002/jcc.540130805" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>]</li><li id='B35-molecules-27-01071' class='html-xx' data-content='35.'>Hess, B.; Bekker, H.; Berendsen, H.J.C.; Fraaije, J.G.E.M. LINCS: A linear constraint solver for molecular simulations. <span class='html-italic'>J. Comput. Chem.</span> <b>1997</b>, <span class='html-italic'>18</span>, 1463–1472. [<a href="https://scholar.google.com/scholar_lookup?title=LINCS:+A+linear+constraint+solver+for+molecular+simulations&author=Hess,+B.&author=Bekker,+H.&author=Berendsen,+H.J.C.&author=Fraaije,+J.G.E.M.&publication_year=1997&journal=J.+Comput.+Chem.&volume=18&pages=1463%E2%80%931472&doi=10.1002/(SICI)1096-987X(199709)18:12%3C1463::AID-JCC4%3E3.0.CO;2-H" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1002/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>]</li><li id='B36-molecules-27-01071' class='html-xx' data-content='36.'>Essmann, U.; Perera, L.; Berkowitz, M.L.; Darden, T.; Lee, H.; Pedersen, L.G. A smooth particle mesh Ewald method. <span class='html-italic'>J. Chem. Phys.</span> <b>1995</b>, <span class='html-italic'>103</span>, 8577–8593. [<a href="https://scholar.google.com/scholar_lookup?title=A+smooth+particle+mesh+Ewald+method&author=Essmann,+U.&author=Perera,+L.&author=Berkowitz,+M.L.&author=Darden,+T.&author=Lee,+H.&author=Pedersen,+L.G.&publication_year=1995&journal=J.+Chem.+Phys.&volume=103&pages=8577%E2%80%938593&doi=10.1063/1.470117" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1063/1.470117" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>] [<a href="http://pdfs.semanticscholar.org/7030/2e07a5d51a7e330c11e61424f6a3beffa0ab.pdf" target='_blank' rel="noopener noreferrer">Green Version</a>]</li><li id='B37-molecules-27-01071' class='html-xx' data-content='37.'>Humphrey, W.F.; Dalke, A.; Schulten, K. VMD: Visual molecular dynamics. <span class='html-italic'>J. Mol. Graph.</span> <b>1996</b>, <span class='html-italic'>14</span>, 33–38. [<a href="https://scholar.google.com/scholar_lookup?title=VMD:+Visual+molecular+dynamics&author=Humphrey,+W.F.&author=Dalke,+A.&author=Schulten,+K.&publication_year=1996&journal=J.+Mol.+Graph.&volume=14&pages=33%E2%80%9338&doi=10.1016/0263-7855(96)00018-5" class='google-scholar' target='_blank' rel='noopener noreferrer'>Google Scholar</a>] [<a href="https://doi.org/10.1016/0263-7855(96)00018-5" class='cross-ref' target='_blank' rel='noopener noreferrer'>CrossRef</a>]</li></ol></section><section id='FiguresandTable' type='display-objects'><div class="html-fig-wrap" id="molecules-27-01071-f002"> <div class='html-fig_img'> <div class="html-figpopup html-figpopup-link" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/27/3/1071/display" href="#fig_body_display_molecules-27-01071-f002"> <img alt="Molecules 27 01071 g002 550" data-large="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g002.png" data-original="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g002.png" data-lsrc="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g002-550.jpg" /> <a class="html-expand html-figpopup" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/27/3/1071/display" href="#fig_body_display_molecules-27-01071-f002"></a> </div> </div> <div class="html-fig_description"> <b>Figure 2.</b> The m-gate electrostatic network in the various mutants (<b>a</b>,<b>c</b>–<b>f</b>) and wild-type (<b>b</b>) of apo AAC. Yellow dash lines are added manually to indicate the salt bridges and H-bonds that do not appear in the shown snapshots. Salt bridges or H-bonds with the occupancies lower than 5% are not shown. For mutants, occupancies of salt bridges and H-bonds are calculated on each trajectory from 200 ns to 1 μs. The occupancies in the <span class='html-italic'>wild-type AAC</span> were averaged over last 2 μs of the three 3-μs trajectories.  </div> </div> <div class="html-fig_show mfp-hide" id ="fig_body_display_molecules-27-01071-f002" > <div class="html-caption" > <b>Figure 2.</b> The m-gate electrostatic network in the various mutants (<b>a</b>,<b>c</b>–<b>f</b>) and wild-type (<b>b</b>) of apo AAC. Yellow dash lines are added manually to indicate the salt bridges and H-bonds that do not appear in the shown snapshots. Salt bridges or H-bonds with the occupancies lower than 5% are not shown. For mutants, occupancies of salt bridges and H-bonds are calculated on each trajectory from 200 ns to 1 μs. The occupancies in the <span class='html-italic'>wild-type AAC</span> were averaged over last 2 μs of the three 3-μs trajectories.</div> <div class="html-img"><img alt="Molecules 27 01071 g002" data-large="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g002.png" data-original="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g002.png" data-lsrc="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g002.png" /></div> </div><div class="html-fig-wrap" id="molecules-27-01071-f003"> <div class='html-fig_img'> <div class="html-figpopup html-figpopup-link" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/27/3/1071/display" href="#fig_body_display_molecules-27-01071-f003"> <img alt="Molecules 27 01071 g003 550" data-large="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g003.png" data-original="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g003.png" data-lsrc="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g003-550.jpg" /> <a class="html-expand html-figpopup" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/27/3/1071/display" href="#fig_body_display_molecules-27-01071-f003"></a> </div> </div> <div class="html-fig_description"> <b>Figure 3.</b> The m-gate electrostatic network in the AAC-CATR complex. Top view (<b>a</b>) and side view (<b>b</b>) of the AAC-CATR interactions in the last simulation snapshot (1 μs). CATR is shown in yellow think sticks. In the side-view figure, protein backbones are shown in transparent cartoon. Yellow dash lines are added manually to indicate the H-bonds that do not appear in the shown snapshot. Q36 forms H-bond with both D231 (occupancy: 71%) and K32 (occupancy: 94%), and these values are not labeled in the figure because of limited space. The H-bonds with the occupancies lower than 5% are not shown. The occupancies are calculated on the trajectory from 200 ns to 1 μs. (<b>c</b>) A schematic representation of the CATR-AAC interactions. The electrostatic interactions between CATR and AAC are shown in cyan lines, and the interactions within the m-gate network are shown in blue lines.  </div> </div> <div class="html-fig_show mfp-hide" id ="fig_body_display_molecules-27-01071-f003" > <div class="html-caption" > <b>Figure 3.</b> The m-gate electrostatic network in the AAC-CATR complex. Top view (<b>a</b>) and side view (<b>b</b>) of the AAC-CATR interactions in the last simulation snapshot (1 μs). CATR is shown in yellow think sticks. In the side-view figure, protein backbones are shown in transparent cartoon. Yellow dash lines are added manually to indicate the H-bonds that do not appear in the shown snapshot. Q36 forms H-bond with both D231 (occupancy: 71%) and K32 (occupancy: 94%), and these values are not labeled in the figure because of limited space. The H-bonds with the occupancies lower than 5% are not shown. The occupancies are calculated on the trajectory from 200 ns to 1 μs. (<b>c</b>) A schematic representation of the CATR-AAC interactions. The electrostatic interactions between CATR and AAC are shown in cyan lines, and the interactions within the m-gate network are shown in blue lines.</div> <div class="html-img"><img alt="Molecules 27 01071 g003" data-large="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g003.png" data-original="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g003.png" data-lsrc="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g003.png" /></div> </div><div class="html-fig-wrap" id="molecules-27-01071-f004"> <div class='html-fig_img'> <div class="html-figpopup html-figpopup-link" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/27/3/1071/display" href="#fig_body_display_molecules-27-01071-f004"> <img alt="Molecules 27 01071 g004 550" data-large="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g004.png" data-original="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g004.png" data-lsrc="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g004-550.jpg" /> <a class="html-expand html-figpopup" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/27/3/1071/display" href="#fig_body_display_molecules-27-01071-f004"></a> </div> </div> <div class="html-fig_description"> <b>Figure 4.</b> Conformations of R137 are quite different with and without presence of CATR. In the crystal structure (<b>a</b>) and the MD simulation structure (<b>b</b>) of CATR-AAC complex, the guanidine group of R137 binds with backbone carbonyl of R71 and fills the gap between the [YWF][KR]G motif and A26. (<b>c</b>) The gap between the [YWF][KR]G motif and A26 is filled with water molecules in the simulations on apo AAC (<span class='html-italic'>wild-type AAC</span>). (<b>d</b>) Sequence logo of A26 and residues involved in the interaction between the [YWF][KR]G motif and Pro kink region in orthologs of AAC, SLC25A42, GDC (graves disease carrier), SCaMC (calcium-binding mitochondrial carrier protein), SLC25A41 and SLC25A43, respectively. Equivalent positions among these paralogs are aligned in the same column. The multiple sequence alignment of SLC25A43 was calculated based on 171 sequences from the UniProt database. The results of other carriers were obtained from our recent work [<a href="#B17-molecules-27-01071" class="html-bibr">17</a>]. The residues are numbered based on hAAC1 (human ADP/ATP carrier), SLC25A42, SLC25A16, SCaMC1, SLC25A41 and SLC25A43, respectively.  </div> </div> <div class="html-fig_show mfp-hide" id ="fig_body_display_molecules-27-01071-f004" > <div class="html-caption" > <b>Figure 4.</b> Conformations of R137 are quite different with and without presence of CATR. In the crystal structure (<b>a</b>) and the MD simulation structure (<b>b</b>) of CATR-AAC complex, the guanidine group of R137 binds with backbone carbonyl of R71 and fills the gap between the [YWF][KR]G motif and A26. (<b>c</b>) The gap between the [YWF][KR]G motif and A26 is filled with water molecules in the simulations on apo AAC (<span class='html-italic'>wild-type AAC</span>). (<b>d</b>) Sequence logo of A26 and residues involved in the interaction between the [YWF][KR]G motif and Pro kink region in orthologs of AAC, SLC25A42, GDC (graves disease carrier), SCaMC (calcium-binding mitochondrial carrier protein), SLC25A41 and SLC25A43, respectively. Equivalent positions among these paralogs are aligned in the same column. The multiple sequence alignment of SLC25A43 was calculated based on 171 sequences from the UniProt database. The results of other carriers were obtained from our recent work [<a href="#B17-molecules-27-01071" class="html-bibr">17</a>]. The residues are numbered based on hAAC1 (human ADP/ATP carrier), SLC25A42, SLC25A16, SCaMC1, SLC25A41 and SLC25A43, respectively.</div> <div class="html-img"><img alt="Molecules 27 01071 g004" data-large="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g004.png" data-original="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g004.png" data-lsrc="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g004.png" /></div> </div><div class="html-fig-wrap" id="molecules-27-01071-f005"> <div class='html-fig_img'> <div class="html-figpopup html-figpopup-link" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/27/3/1071/display" href="#fig_body_display_molecules-27-01071-f005"> <img alt="Molecules 27 01071 g005 550" data-large="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g005.png" data-original="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g005.png" data-lsrc="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g005-550.jpg" /> <a class="html-expand html-figpopup" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/27/3/1071/display" href="#fig_body_display_molecules-27-01071-f005"></a> </div> </div> <div class="html-fig_description"> <b>Figure 5.</b> Structures and dynamics of AAC were not significantly affected in the <span class='html-italic'>all3A-AAC</span>, <span class='html-italic'>R235A-AAC</span> and <span class='html-italic'>R279A-AAC</span> mutants. (<b>a</b>–<b>c</b>) RMSF of three mutants compared to that of <span class='html-italic'>wild-type AAC</span>. The RMSF were calculated on each trajectory from 200 ns to 1 μs. (<b>d</b>–<b>f</b>) Superposition of the structures at the end of the simulation (1 μs) to the crystal structure (PDB:1OKC).  </div> </div> <div class="html-fig_show mfp-hide" id ="fig_body_display_molecules-27-01071-f005" > <div class="html-caption" > <b>Figure 5.</b> Structures and dynamics of AAC were not significantly affected in the <span class='html-italic'>all3A-AAC</span>, <span class='html-italic'>R235A-AAC</span> and <span class='html-italic'>R279A-AAC</span> mutants. (<b>a</b>–<b>c</b>) RMSF of three mutants compared to that of <span class='html-italic'>wild-type AAC</span>. The RMSF were calculated on each trajectory from 200 ns to 1 μs. (<b>d</b>–<b>f</b>) Superposition of the structures at the end of the simulation (1 μs) to the crystal structure (PDB:1OKC).</div> <div class="html-img"><img alt="Molecules 27 01071 g005" data-large="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g005.png" data-original="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g005.png" data-lsrc="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g005.png" /></div> </div><div class="html-fig-wrap" id="molecules-27-01071-f006"> <div class='html-fig_img'> <div class="html-figpopup html-figpopup-link" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/27/3/1071/display" href="#fig_body_display_molecules-27-01071-f006"> <img alt="Molecules 27 01071 g006 550" data-large="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g006.png" data-original="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g006.png" data-lsrc="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g006-550.jpg" /> <a class="html-expand html-figpopup" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/27/3/1071/display" href="#fig_body_display_molecules-27-01071-f006"></a> </div> </div> <div class="html-fig_description"> <b>Figure 6.</b> The R79A mutation causes drastic conformational change around C1 loop. (<b>a</b>) RMSF of the mutant compared to that of <span class='html-italic'>wild-type AAC</span>. The RMSF were calculated on each trajectory from 200 ns to 1 μs. (<b>b</b>) Superposition of the structures at the end of the simulations of <span class='html-italic'>R79A-AAC</span> and <span class='html-italic'>wild-type AAC</span> (1.5 μs). (<b>c</b>) Time evolution of the minimum distance between R104 and D195 heavy atoms during the simulations. (<b>d</b>) A big crevice formed between the cytoplasmic halves of H3 and H4.  </div> </div> <div class="html-fig_show mfp-hide" id ="fig_body_display_molecules-27-01071-f006" > <div class="html-caption" > <b>Figure 6.</b> The R79A mutation causes drastic conformational change around C1 loop. (<b>a</b>) RMSF of the mutant compared to that of <span class='html-italic'>wild-type AAC</span>. The RMSF were calculated on each trajectory from 200 ns to 1 μs. (<b>b</b>) Superposition of the structures at the end of the simulations of <span class='html-italic'>R79A-AAC</span> and <span class='html-italic'>wild-type AAC</span> (1.5 μs). (<b>c</b>) Time evolution of the minimum distance between R104 and D195 heavy atoms during the simulations. (<b>d</b>) A big crevice formed between the cytoplasmic halves of H3 and H4.</div> <div class="html-img"><img alt="Molecules 27 01071 g006" data-large="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g006.png" data-original="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g006.png" data-lsrc="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g006.png" /></div> </div><div class="html-fig-wrap" id="molecules-27-01071-f007"> <div class='html-fig_img'> <div class="html-figpopup html-figpopup-link" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/27/3/1071/display" href="#fig_body_display_molecules-27-01071-f007"> <img alt="Molecules 27 01071 g007 550" data-large="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g007.png" data-original="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g007.png" data-lsrc="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g007-550.jpg" /> <a class="html-expand html-figpopup" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/27/3/1071/display" href="#fig_body_display_molecules-27-01071-f007"></a> </div> </div> <div class="html-fig_description"> <b>Figure 7.</b> Changes in the structure and dynamics in <span class='html-italic'>all4A-AAC</span>. (<b>a</b>) Superposition of the structures at the end of the simulation (1 μs) to the crystal structure (PDB: 1OKC). The H2, C1 loop, H3 and M2 loop of the simulated structure are present in cartoon mode and highlighted in orange. (<b>b</b>) RMSF of <span class='html-italic'>all4A-AAC</span> compared to that of <span class='html-italic'>wild-type AAC</span>. The RMSF were calculated on each trajectory from 200 ns to 1 μs. (<b>c</b>) A crevice formed between the matrix end of H3 and the β-turn structure of the [YWF][KR]G motif which allows for the passing through of the solvent. (<b>d</b>) The crevice between H2 and H3 interface became closed after transient opening.  </div> </div> <div class="html-fig_show mfp-hide" id ="fig_body_display_molecules-27-01071-f007" > <div class="html-caption" > <b>Figure 7.</b> Changes in the structure and dynamics in <span class='html-italic'>all4A-AAC</span>. (<b>a</b>) Superposition of the structures at the end of the simulation (1 μs) to the crystal structure (PDB: 1OKC). The H2, C1 loop, H3 and M2 loop of the simulated structure are present in cartoon mode and highlighted in orange. (<b>b</b>) RMSF of <span class='html-italic'>all4A-AAC</span> compared to that of <span class='html-italic'>wild-type AAC</span>. The RMSF were calculated on each trajectory from 200 ns to 1 μs. (<b>c</b>) A crevice formed between the matrix end of H3 and the β-turn structure of the [YWF][KR]G motif which allows for the passing through of the solvent. (<b>d</b>) The crevice between H2 and H3 interface became closed after transient opening.</div> <div class="html-img"><img alt="Molecules 27 01071 g007" data-large="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g007.png" data-original="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g007.png" data-lsrc="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g007.png" /></div> </div><div class="html-fig-wrap" id="molecules-27-01071-f008"> <div class='html-fig_img'> <div class="html-figpopup html-figpopup-link" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/27/3/1071/display" href="#fig_body_display_molecules-27-01071-f008"> <img alt="Molecules 27 01071 g008 550" data-large="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g008.png" data-original="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g008.png" data-lsrc="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g008-550.jpg" /> <a class="html-expand html-figpopup" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/27/3/1071/display" href="#fig_body_display_molecules-27-01071-f008"></a> </div> </div> <div class="html-fig_description"> <b>Figure 8.</b> Geometrical symmetry around the m-gate level in c-state AAC. (<b>a</b>) The model used to calculate deviations from the C<sub>3</sub>-symmetry score. The triplets used for calculation are shown in spheres. (<b>b</b>) The average ψ values of the <span class='html-italic'>wild-type</span> simulation structure and crystal structure of c-state AAC (PDB: 1OKC). (<b>c</b>–<b>h</b>) Time evolution of the geometric symmetry analysis in <span class='html-italic'>wild-type AAC</span> and the five mutants. Gradient colors are used to indicate the extent to which each plane deviates from C<sub>3</sub>-symmetry.  </div> </div> <div class="html-fig_show mfp-hide" id ="fig_body_display_molecules-27-01071-f008" > <div class="html-caption" > <b>Figure 8.</b> Geometrical symmetry around the m-gate level in c-state AAC. (<b>a</b>) The model used to calculate deviations from the C<sub>3</sub>-symmetry score. The triplets used for calculation are shown in spheres. (<b>b</b>) The average ψ values of the <span class='html-italic'>wild-type</span> simulation structure and crystal structure of c-state AAC (PDB: 1OKC). (<b>c</b>–<b>h</b>) Time evolution of the geometric symmetry analysis in <span class='html-italic'>wild-type AAC</span> and the five mutants. Gradient colors are used to indicate the extent to which each plane deviates from C<sub>3</sub>-symmetry.</div> <div class="html-img"><img alt="Molecules 27 01071 g008" data-large="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g008.png" data-original="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g008.png" data-lsrc="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g008.png" /></div> </div><div class="html-fig-wrap" id="molecules-27-01071-f009"> <div class='html-fig_img'> <div class="html-figpopup html-figpopup-link" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/27/3/1071/display" href="#fig_body_display_molecules-27-01071-f009"> <img alt="Molecules 27 01071 g009 550" data-large="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g009.png" data-original="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g009.png" data-lsrc="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g009-550.jpg" /> <a class="html-expand html-figpopup" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/27/3/1071/display" href="#fig_body_display_molecules-27-01071-f009"></a> </div> </div> <div class="html-fig_description"> <b>Figure 9.</b> Sequence logo presentation of 53 human mitochondria carriers. Only residues around the m-gate level in odd-numbered helices (<b>left</b>) and even-numbered helices (<b>right</b>) are shown. Triplet positions at least with one charged residue in AAC are highlighted with red arrows.  </div> </div> <div class="html-fig_show mfp-hide" id ="fig_body_display_molecules-27-01071-f009" > <div class="html-caption" > <b>Figure 9.</b> Sequence logo presentation of 53 human mitochondria carriers. Only residues around the m-gate level in odd-numbered helices (<b>left</b>) and even-numbered helices (<b>right</b>) are shown. Triplet positions at least with one charged residue in AAC are highlighted with red arrows.</div> <div class="html-img"><img alt="Molecules 27 01071 g009" data-large="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g009.png" data-original="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g009.png" data-lsrc="/molecules/molecules-27-01071/article_deploy/html/images/molecules-27-01071-g009.png" /></div> </div><div class="html-table-wrap" id="molecules-27-01071-t001"> <div class="html-table_wrap_td" > <div class="html-tablepopup html-tablepopup-link" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/27/3/1071/display" href='#table_body_display_molecules-27-01071-t001'> <img alt="Table" data-lsrc="https://www.mdpi.com/img/table.png" /> <a class="html-expand html-tablepopup" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/27/3/1071/display" href="#table_body_display_molecules-27-01071-t001"></a> </div> </div> <div class="html-table_wrap_discription"> <b>Table 1.</b> Summary of simulations in the current work. </div> </div> <div class="html-table_show mfp-hide " id ="table_body_display_molecules-27-01071-t001" > <div class="html-caption" ><b>Table 1.</b> Summary of simulations in the current work.</div> <table > <thead ><tr ><th align='center' valign='middle' style='border-top:solid thin;border-bottom:solid thin' class='html-align-center' >System</th><th align='center' valign='middle' style='border-top:solid thin;border-bottom:solid thin' class='html-align-center' >Mutations</th><th align='center' valign='middle' style='border-top:solid thin;border-bottom:solid thin' class='html-align-center' >Simulation Time</th></tr></thead><tbody ><tr ><td align='center' valign='middle' class='html-align-center' ><span class='html-italic'>all4A-AAC</span></td><td align='center' valign='middle' class='html-align-center' >K22A + R79A + R235A + R279A</td><td align='center' valign='middle' class='html-align-center' >1.5 μs</td></tr><tr ><td align='center' valign='middle' class='html-align-center' ><span class='html-italic'>all3A-AAC</span></td><td align='center' valign='middle' class='html-align-center' >K22A + R79A + R279A</td><td align='center' valign='middle' class='html-align-center' >1 μs</td></tr><tr ><td align='center' valign='middle' class='html-align-center' ><span class='html-italic'>R279A-AAC</span></td><td align='center' valign='middle' class='html-align-center' >K22A + R279A</td><td align='center' valign='middle' class='html-align-center' >1 μs</td></tr><tr ><td align='center' valign='middle' class='html-align-center' ><span class='html-italic'>R235A-AAC</span></td><td align='center' valign='middle' class='html-align-center' >K22A + R235A</td><td align='center' valign='middle' class='html-align-center' >1 μs</td></tr><tr ><td align='center' valign='middle' class='html-align-center' ><span class='html-italic'>R79A-AAC</span></td><td align='center' valign='middle' class='html-align-center' >K22A + R79A</td><td align='center' valign='middle' class='html-align-center' >1.5 μs</td></tr><tr ><td align='center' valign='middle' style='border-bottom:solid thin' class='html-align-center' ><span class='html-italic'>CATR-AAC</span></td><td align='center' valign='middle' style='border-bottom:solid thin' class='html-align-center' >/</td><td align='center' valign='middle' style='border-bottom:solid thin' class='html-align-center' >1 μs</td></tr></tbody> </table> </div></section><section class='html-fn_group'><table><tr id=''><td></td><td><div class='html-p'><b>Publisher’s Note:</b> MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.</div></td></tr></table></section> <section id="html-copyright"><br>© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<a href='https://creativecommons.org/licenses/by/4.0/' target='_blank' rel="noopener noreferrer" >https://creativecommons.org/licenses/by/4.0/</a>).</section> </div> </div> <div class="additional-content"> <h2><a name="cite"></a>Share and Cite</h2> <div class="social-media-links" style="text-align: left;"> <a href="/cdn-cgi/l/email-protection#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" title="Email"> <i class="fa fa-envelope-square" style="font-size: 30px;"></i> </a> <a href="https://twitter.com/intent/tweet?text=Investigating+the+Broad+Matrix-Gate+Network+in+the+Mitochondrial+ADP%2FATP+Carrier+through+Molecular+Dynamics+Simulations&hashtags=mdpimolecules&url=https%3A%2F%2Fwww.mdpi.com%2F1485542&via=Molecules_MDPI" onclick="windowOpen(this.href,600,800); return false" target="_blank" rel="noopener noreferrer"> <i class="fa fa-twitter-x-square" style="font-size: 30px;"></i> </a> <a href=" http://www.linkedin.com/shareArticle?mini=true&url=https%3A%2F%2Fwww.mdpi.com%2F1485542&title=Investigating%20the%20Broad%20Matrix-Gate%20Network%20in%20the%20Mitochondrial%20ADP%2FATP%20Carrier%20through%20Molecular%20Dynamics%20Simulations%26source%3Dhttps%3A%2F%2Fwww.mdpi.com%26summary%3DThe%20mitochondrial%20ADP%2FATP%20carrier%20%28AAC%29%20exports%20ATP%20and%20imports%20ADP%20through%20alternating%20between%20cytosol-open%20%28c-%29%20and%20matrix-open%20%28m-%29%20states.%20The%20salt%20bridge%20networks%20near%20the%20matrix%20side%20%28m-gate%29%20and%20cytosol%20side%20%28c-gate%29%20are%20thought%20to%20be%20crucial%20%5B...%5D" onclick="windowOpen(this.href,600,800); return false" title="LinkedIn" target="_blank" rel="noopener noreferrer"> <i class="fa fa-linkedin-square" style="font-size: 30px;"></i> </a> <a href="https://www.facebook.com/sharer.php?u=https://www.mdpi.com/1485542" title="facebook" target="_blank" rel="noopener noreferrer"> <i class="fa fa-facebook-square" style="font-size: 30px;"></i> </a> <a href="javascript:void(0);" title="Wechat" data-reveal-id="weixin-share-modal"> <i class="fa fa-weixin-square" style="font-size: 26px;"></i> </a> <a href="http://www.reddit.com/submit?url=https://www.mdpi.com/1485542" title="Reddit" target="_blank" rel="noopener noreferrer"> <i class="fa fa-reddit-square" style="font-size: 30px;"></i> </a> <a href="http://www.mendeley.com/import/?url=https://www.mdpi.com/1485542" title="Mendeley" target="_blank" rel="noopener noreferrer"> <i class="fa fa-mendeley-square" style="font-size: 30px;"></i> </a> </div> <div class="in-tab" style="padding-top: 0px!important; margin-top: 15px;"> <div><b>MDPI and ACS Style</b></div> <p> Yao, S.; Ma, B.; Yi, Q.; Guan, M.-X.; Cang, X. Investigating the Broad Matrix-Gate Network in the Mitochondrial ADP/ATP Carrier through Molecular Dynamics Simulations. <em>Molecules</em> <b>2022</b>, <em>27</em>, 1071. https://doi.org/10.3390/molecules27031071 </p> <div style="display: block"> <b>AMA Style</b><br> <p> Yao S, Ma B, Yi Q, Guan M-X, Cang X. Investigating the Broad Matrix-Gate Network in the Mitochondrial ADP/ATP Carrier through Molecular Dynamics Simulations. <em>Molecules</em>. 2022; 27(3):1071. https://doi.org/10.3390/molecules27031071 </p> <b>Chicago/Turabian Style</b><br> <p> Yao, Shihao, Boyuan Ma, Qiuzi Yi, Min-Xin Guan, and Xiaohui Cang. 2022. "Investigating the Broad Matrix-Gate Network in the Mitochondrial ADP/ATP Carrier through Molecular Dynamics Simulations" <em>Molecules</em> 27, no. 3: 1071. https://doi.org/10.3390/molecules27031071 </p> <b>APA Style</b><br> <p> Yao, S., Ma, B., Yi, Q., Guan, M.-X., & Cang, X. (2022). Investigating the Broad Matrix-Gate Network in the Mitochondrial ADP/ATP Carrier through Molecular Dynamics Simulations. <em>Molecules</em>, <em>27</em>(3), 1071. https://doi.org/10.3390/molecules27031071 </p> </div> </div> <h2><a name="metrics"></a>Article Metrics</h2> <div class="row"> <div class="small-12 columns"> <div id="loaded_cite_count" style="display:none">No</div> <div id="framed_div_cited_count" class="in-tab" style="display: none; overflow: auto;"></div> <div id="loaded" style="display:none">No</div> <div id="framed_div" class="in-tab" style="display: none; margin-top: 10px;"></div> </div> <div class="small-12 columns"> <div id="article_stats_div" style="display: none; margin-bottom: 1em;"> <h3>Article Access Statistics</h3> <div id="article_stats_swf" ></div> For more information on the journal statistics, click <a href="/journal/molecules/stats">here</a>. <div class="info-box"> Multiple requests from the same IP address are counted as one view. </div> </div> </div> </div> </div> </div> </article> </div> <div id="supplementaryModal" class="reveal-modal reveal-modal-new" data-reveal aria-labelledby="Captcha" aria-hidden="true" role="dialog"> <div class="row"> <div class="large-12 medium-12 small-12 columns"> <h2>Supplementary Material</h2> <div class="custom-accordion-for-small-screen-content show-for-medium-up"> <div class="in-tab"> <ul style="margin:0; list-style: none; overflow: auto;"> <li><a name="supplementary_file1"></a><b>Supplementary File 1:</b> <p> <a href="/1420-3049/27/3/1071/s1?version=1644059025"> ZIP-Document </a> (ZIP, 910 KiB) </p> </li> </ul> </div> </div> </div> </div> <a class="close-reveal-modal" aria-label="Close"> <i class="material-icons">clear</i> </a> </div> </div></div> <div class="webpymol-controls webpymol-controls-template" style="margin-top: 10px; display: none;"> <a class="bzoom">Zoom</a> <span style="display: inline-block; margin-left: 5px; margin-right: 5px;">|</span> <a class="borient"> Orient </a> <span style="display: inline-block; margin-left: 5px; margin-right: 5px;">|</span> <a class="blines"> As Lines </a> <span style="display: inline-block; margin-left: 5px; margin-right: 5px;">|</span> <a class="bsticks"> As Sticks </a> <span style="display: inline-block; margin-left: 5px; margin-right: 5px;">|</span> <a class="bcartoon"> As Cartoon </a> <span style="display: inline-block; margin-left: 5px; margin-right: 5px;">|</span> <a class="bsurface"> As Surface </a> <span style="display: inline-block; margin-left: 5px; margin-right: 5px;">|</span> <a class="bprevscene">Previous Scene</a> <span style="display: inline-block; margin-left: 5px; margin-right: 5px;">|</span> <a class="bnextscene">Next Scene</a> </div> <div id="scifeed-modal" class="reveal-modal reveal-modal-new" data-reveal aria-labelledby="modalTitle" aria-hidden="true" role="dialog"> </div> <div id="recommended-articles-modal" class="reveal-modal reveal-modal-new" data-reveal aria-labelledby="modalTitle" aria-hidden="true" role="dialog"> </div> <div id="author-biographies-modal" class="reveal-modal reveal-modal-new" data-reveal aria-labelledby="modalTitle" aria-hidden="true" role="dialog"> </div> <div id="cite-modal" class="reveal-modal reveal-modal-new" data-reveal aria-labelledby="Captcha" aria-hidden="true" role="dialog"> <div class="row"> <div class="small-12 columns"> <h2 style="margin: 0;">Cite</h2> </div> <div class="small-12 columns">  <form style="margin:0; padding:0; display:inline;" name="export-bibtex" method="POST" action="/export"> <input type="hidden" name="articles_ids[]" value="742771"> <input type="hidden" name="export_format_top" value="bibtex"> <input type="hidden" name="export_submit_top" value=""> </form>  <form style="margin:0; padding:0; display:inline;" name="export-endnote" method="POST" action="/export"> <input type="hidden" name="articles_ids[]" value="742771"> <input type="hidden" name="export_format_top" value="endnote_no_abstract"> <input type="hidden" name="export_submit_top" value=""> </form>  <form style="margin:0; padding:0; display:inline;" name="export-ris" method="POST" action="/export"> <input type="hidden" name="articles_ids[]" value="742771"> <input type="hidden" name="export_format_top" value="ris"> <input type="hidden" name="export_submit_top" value=""> </form> <div> Export citation file: <a href="javascript:window.document.forms['export-bibtex'].submit()">BibTeX</a> | <a href="javascript:window.document.forms['export-endnote'].submit()">EndNote</a> | <a href="javascript:window.document.forms['export-ris'].submit()">RIS</a> </div> </div> <div class="small-12 columns"> <div class="in-tab"> <div><b>MDPI and ACS Style</b></div> <p> Yao, S.; Ma, B.; Yi, Q.; Guan, M.-X.; Cang, X. Investigating the Broad Matrix-Gate Network in the Mitochondrial ADP/ATP Carrier through Molecular Dynamics Simulations. <em>Molecules</em> <b>2022</b>, <em>27</em>, 1071. https://doi.org/10.3390/molecules27031071 </p> <div style="display: block"> <b>AMA Style</b><br> <p> Yao S, Ma B, Yi Q, Guan M-X, Cang X. Investigating the Broad Matrix-Gate Network in the Mitochondrial ADP/ATP Carrier through Molecular Dynamics Simulations. <em>Molecules</em>. 2022; 27(3):1071. https://doi.org/10.3390/molecules27031071 </p> <b>Chicago/Turabian Style</b><br> <p> Yao, Shihao, Boyuan Ma, Qiuzi Yi, Min-Xin Guan, and Xiaohui Cang. 2022. "Investigating the Broad Matrix-Gate Network in the Mitochondrial ADP/ATP Carrier through Molecular Dynamics Simulations" <em>Molecules</em> 27, no. 3: 1071. https://doi.org/10.3390/molecules27031071 </p> <b>APA Style</b><br> <p> Yao, S., Ma, B., Yi, Q., Guan, M.-X., & Cang, X. (2022). Investigating the Broad Matrix-Gate Network in the Mitochondrial ADP/ATP Carrier through Molecular Dynamics Simulations. <em>Molecules</em>, <em>27</em>(3), 1071. https://doi.org/10.3390/molecules27031071 </p> </div> </div> </div> </div> <a class="close-reveal-modal" aria-label="Close"> <i class="material-icons">clear</i> </a> </div> </div> </div> </div> </div> </section> <div id="footer"> <div class="journal-info"> <span> <em><a class="Var_JournalInfo" href="/journal/molecules">Molecules</a></em>, EISSN 1420-3049, Published by MDPI </span> <div class="large-right"> <span> <a href="/rss/journal/molecules" class="rss-link">RSS</a> </span> <span> <a href="/journal/molecules/toc-alert">Content Alert</a> </span> </div> </div> <div class="row full-width footer-links" data-equalizer="footer" data-equalizer-mq="small"> <div class="large-2 large-push-4 medium-3 small-6 columns" data-equalizer-watch="footer"> <h3> Further Information </h3> <a href="/apc"> Article Processing Charges </a> <a href="/about/payment"> Pay an Invoice </a> <a href="/openaccess"> Open Access Policy </a> <a href="/about/contact"> Contact MDPI </a> <a href="https://careers.mdpi.com" target="_blank" rel="noopener noreferrer"> Jobs at MDPI </a> </div> <div class="large-2 large-push-4 medium-3 small-6 columns" data-equalizer-watch="footer"> <h3> Guidelines </h3> <a href="/authors"> For Authors </a> <a href="/reviewers"> For Reviewers </a> <a href="/editors"> For Editors </a> <a href="/librarians"> For Librarians </a> <a href="/publishing_services"> For Publishers </a> <a href="/societies"> For Societies </a> <a href="/conference_organizers"> For Conference Organizers </a> </div> <div class="large-2 large-push-4 medium-3 small-6 columns"> <h3> MDPI Initiatives </h3> <a href="https://sciforum.net" target="_blank" rel="noopener noreferrer"> Sciforum </a> <a href="https://www.mdpi.com/books" target="_blank" rel="noopener noreferrer"> MDPI Books </a> <a href="https://www.preprints.org" target="_blank" rel="noopener noreferrer"> Preprints.org </a> <a href="https://www.scilit.com" target="_blank" rel="noopener noreferrer"> Scilit </a> <a href="https://sciprofiles.com?utm_source=mpdi.com&utm_medium=bottom_menu&utm_campaign=initiative" target="_blank" rel="noopener noreferrer"> SciProfiles </a> <a href="https://encyclopedia.pub" target="_blank" rel="noopener noreferrer"> Encyclopedia </a> <a href="https://jams.pub" target="_blank" rel="noopener noreferrer"> JAMS </a> <a href="/about/proceedings"> Proceedings Series </a> </div> <div class="large-2 large-push-4 medium-3 small-6 right-border-large-without columns UA_FooterFollowMDPI"> <h3> Follow MDPI </h3> <a href="https://www.linkedin.com/company/mdpi" target="_blank" rel="noopener noreferrer"> LinkedIn </a> <a href="https://www.facebook.com/MDPIOpenAccessPublishing" target="_blank" rel="noopener noreferrer"> Facebook </a> <a href="https://twitter.com/MDPIOpenAccess" target="_blank" rel="noopener noreferrer"> Twitter </a> </div> <div id="footer-subscribe" class="large-4 large-pull-8 medium-12 small-12 left-border-large columns"> <div class="footer-subscribe__container"> <img class="show-for-large-up" src="https://pub.mdpi-res.com/img/design/mdpi-pub-logo-white-small.png?71d18e5f805839ab?1739526160" alt="MDPI" title="MDPI Open Access Journals" style="height: 50px; margin-bottom: 10px;"> <form id="newsletter" method="POST" action="/subscribe"> <p> Subscribe to receive issue release notifications and newsletters from MDPI journals </p> <select multiple id="newsletter-journal" class="foundation-select" name="journals[]"> <option value="acoustics">Acoustics</option> <option value="amh">Acta Microbiologica Hellenica</option> <option value="actuators">Actuators</option> <option value="adhesives">Adhesives</option> <option value="admsci">Administrative Sciences</option> <option value="adolescents">Adolescents</option> <option value="arm">Advances in Respiratory Medicine</option> <option value="aerobiology">Aerobiology</option> <option value="aerospace">Aerospace</option> <option value="agriculture">Agriculture</option> <option value="agriengineering">AgriEngineering</option> <option value="agrochemicals">Agrochemicals</option> <option value="agronomy">Agronomy</option> <option value="ai">AI</option> <option value="aisens">AI Sensors</option> <option value="air">Air</option> <option value="algorithms">Algorithms</option> <option value="allergies">Allergies</option> <option value="alloys">Alloys</option> <option value="analytica">Analytica</option> <option value="analytics">Analytics</option> <option value="anatomia">Anatomia</option> <option value="anesthres">Anesthesia Research</option> <option value="animals">Animals</option> <option value="antibiotics">Antibiotics</option> <option value="antibodies">Antibodies</option> <option value="antioxidants">Antioxidants</option> <option value="applbiosci">Applied Biosciences</option> <option value="applmech">Applied Mechanics</option> <option value="applmicrobiol">Applied Microbiology</option> <option value="applnano">Applied Nano</option> <option value="applsci">Applied Sciences</option> <option value="asi">Applied System Innovation</option> <option value="appliedchem">AppliedChem</option> <option value="appliedmath">AppliedMath</option> <option value="aquacj">Aquaculture Journal</option> <option value="architecture">Architecture</option> <option value="arthropoda">Arthropoda</option> <option value="arts">Arts</option> <option value="astronomy">Astronomy</option> <option value="atmosphere">Atmosphere</option> <option value="atoms">Atoms</option> <option value="audiolres">Audiology Research</option> <option value="automation">Automation</option> <option value="axioms">Axioms</option> <option value="bacteria">Bacteria</option> <option value="batteries">Batteries</option> <option value="behavsci">Behavioral Sciences</option> <option value="beverages">Beverages</option> <option value="BDCC">Big Data and Cognitive Computing</option> <option value="biochem">BioChem</option> <option value="bioengineering">Bioengineering</option> <option value="biologics">Biologics</option> <option value="biology">Biology</option> <option value="blsf">Biology and Life Sciences Forum</option> <option value="biomass">Biomass</option> <option value="biomechanics">Biomechanics</option> <option value="biomed">BioMed</option> <option value="biomedicines">Biomedicines</option> <option value="biomedinformatics">BioMedInformatics</option> <option value="biomimetics">Biomimetics</option> <option value="biomolecules">Biomolecules</option> <option value="biophysica">Biophysica</option> <option value="biosensors">Biosensors</option> <option value="biosphere">Biosphere</option> <option value="biotech">BioTech</option> <option value="birds">Birds</option> <option value="blockchains">Blockchains</option> <option value="brainsci">Brain Sciences</option> <option value="buildings">Buildings</option> <option value="businesses">Businesses</option> <option value="carbon">C</option> <option value="cancers">Cancers</option> <option value="cardiogenetics">Cardiogenetics</option> <option value="catalysts">Catalysts</option> <option value="cells">Cells</option> <option value="ceramics">Ceramics</option> <option value="challenges">Challenges</option> <option value="ChemEngineering">ChemEngineering</option> <option value="chemistry">Chemistry</option> <option value="chemproc">Chemistry Proceedings</option> <option value="chemosensors">Chemosensors</option> <option value="children">Children</option> <option value="chips">Chips</option> <option value="civileng">CivilEng</option> <option value="cleantechnol">Clean Technologies</option> <option value="climate">Climate</option> <option value="ctn">Clinical and Translational Neuroscience</option> <option value="clinbioenerg">Clinical Bioenergetics</option> <option value="clinpract">Clinics and Practice</option> <option value="clockssleep">Clocks & Sleep</option> <option value="coasts">Coasts</option> <option value="coatings">Coatings</option> <option value="colloids">Colloids and Interfaces</option> <option value="colorants">Colorants</option> <option value="commodities">Commodities</option> <option value="complications">Complications</option> <option value="compounds">Compounds</option> <option value="computation">Computation</option> <option value="csmf">Computer Sciences & Mathematics Forum</option> <option value="computers">Computers</option> <option value="condensedmatter">Condensed Matter</option> <option value="conservation">Conservation</option> <option value="constrmater">Construction Materials</option> <option value="cmd">Corrosion and Materials Degradation</option> <option value="cosmetics">Cosmetics</option> <option value="covid">COVID</option> <option value="cmtr">Craniomaxillofacial Trauma & Reconstruction</option> <option value="crops">Crops</option> <option value="cryo">Cryo</option> <option value="cryptography">Cryptography</option> <option value="crystals">Crystals</option> <option value="cimb">Current Issues in Molecular Biology</option> <option value="curroncol">Current Oncology</option> <option value="dairy">Dairy</option> <option value="data">Data</option> <option value="dentistry">Dentistry Journal</option> <option value="dermato">Dermato</option> <option value="dermatopathology">Dermatopathology</option> <option value="designs">Designs</option> <option value="diabetology">Diabetology</option> <option value="diagnostics">Diagnostics</option> <option value="dietetics">Dietetics</option> <option value="digital">Digital</option> <option value="disabilities">Disabilities</option> <option value="diseases">Diseases</option> <option value="diversity">Diversity</option> <option value="dna">DNA</option> <option value="drones">Drones</option> <option value="ddc">Drugs and Drug Candidates</option> <option value="dynamics">Dynamics</option> <option value="earth">Earth</option> <option value="ecologies">Ecologies</option> <option value="econometrics">Econometrics</option> <option value="economies">Economies</option> <option value="education">Education Sciences</option> <option value="electricity">Electricity</option> <option value="electrochem">Electrochem</option> <option value="electronicmat">Electronic Materials</option> <option value="electronics">Electronics</option> <option value="ecm">Emergency Care and Medicine</option> <option value="encyclopedia">Encyclopedia</option> <option value="endocrines">Endocrines</option> <option value="energies">Energies</option> <option value="esa">Energy Storage and Applications</option> <option value="eng">Eng</option> <option value="engproc">Engineering Proceedings</option> <option value="entropy">Entropy</option> <option value="eesp">Environmental and Earth Sciences Proceedings</option> <option value="environments">Environments</option> <option value="epidemiologia">Epidemiologia</option> <option value="epigenomes">Epigenomes</option> <option value="ebj">European Burn Journal</option> <option value="ejihpe">European Journal of Investigation in Health, Psychology and Education</option> <option value="fermentation">Fermentation</option> <option value="fibers">Fibers</option> <option value="fintech">FinTech</option> <option value="fire">Fire</option> <option value="fishes">Fishes</option> <option value="fluids">Fluids</option> <option value="foods">Foods</option> <option value="forecasting">Forecasting</option> <option value="forensicsci">Forensic Sciences</option> <option value="forests">Forests</option> <option value="fossstud">Fossil Studies</option> <option value="foundations">Foundations</option> <option value="fractalfract">Fractal and Fractional</option> <option value="fuels">Fuels</option> <option value="future">Future</option> <option value="futureinternet">Future Internet</option> <option value="futurepharmacol">Future Pharmacology</option> <option value="futuretransp">Future Transportation</option> <option value="galaxies">Galaxies</option> <option value="games">Games</option> <option value="gases">Gases</option> <option value="gastroent">Gastroenterology Insights</option> <option value="gastrointestdisord">Gastrointestinal Disorders</option> <option value="gastronomy">Gastronomy</option> <option value="gels">Gels</option> <option value="genealogy">Genealogy</option> <option value="genes">Genes</option> <option value="geographies">Geographies</option> <option value="geohazards">GeoHazards</option> <option value="geomatics">Geomatics</option> <option value="geometry">Geometry</option> <option value="geosciences">Geosciences</option> <option value="geotechnics">Geotechnics</option> <option value="geriatrics">Geriatrics</option> <option value="glacies">Glacies</option> <option value="gucdd">Gout, Urate, and Crystal Deposition Disease</option> <option value="grasses">Grasses</option> <option value="greenhealth">Green Health</option> <option value="hardware">Hardware</option> <option value="healthcare">Healthcare</option> <option value="hearts">Hearts</option> <option value="hemato">Hemato</option> <option value="hematolrep">Hematology Reports</option> <option value="heritage">Heritage</option> <option value="histories">Histories</option> <option value="horticulturae">Horticulturae</option> <option value="hospitals">Hospitals</option> <option value="humanities">Humanities</option> <option value="humans">Humans</option> <option value="hydrobiology">Hydrobiology</option> <option value="hydrogen">Hydrogen</option> <option value="hydrology">Hydrology</option> <option value="hygiene">Hygiene</option> <option value="immuno">Immuno</option> <option value="idr">Infectious Disease Reports</option> <option value="informatics">Informatics</option> <option value="information">Information</option> <option value="infrastructures">Infrastructures</option> <option value="inorganics">Inorganics</option> <option value="insects">Insects</option> <option value="instruments">Instruments</option> <option value="iic">Intelligent Infrastructure and Construction</option> <option value="ijerph">International Journal of Environmental Research and Public Health</option> <option value="ijfs">International Journal of Financial Studies</option> <option value="ijms">International Journal of Molecular Sciences</option> <option value="IJNS">International Journal of Neonatal Screening</option> <option value="ijom">International Journal of Orofacial Myology and Myofunctional Therapy</option> <option value="ijpb">International Journal of Plant Biology</option> <option value="ijt">International Journal of Topology</option> <option value="ijtm">International Journal of Translational Medicine</option> <option value="ijtpp">International Journal of Turbomachinery, Propulsion and Power</option> <option value="ime">International Medical Education</option> <option value="inventions">Inventions</option> <option value="IoT">IoT</option> <option value="ijgi">ISPRS International Journal of Geo-Information</option> <option value="J">J</option> <option value="jal">Journal of Ageing and Longevity</option> <option value="jcdd">Journal of Cardiovascular Development and Disease</option> <option value="jcto">Journal of Clinical & Translational Ophthalmology</option> <option value="jcm">Journal of Clinical Medicine</option> <option value="jcs">Journal of Composites Science</option> <option value="jcp">Journal of Cybersecurity and Privacy</option> <option value="jdad">Journal of Dementia and Alzheimer's Disease</option> <option value="jdb">Journal of Developmental Biology</option> <option value="jeta">Journal of Experimental and Theoretical Analyses</option> <option value="jemr">Journal of Eye Movement Research</option> <option value="jfb">Journal of Functional Biomaterials</option> <option value="jfmk">Journal of Functional Morphology and Kinesiology</option> <option value="jof">Journal of Fungi</option> <option value="jimaging">Journal of Imaging</option> <option value="jintelligence">Journal of Intelligence</option> <option value="jlpea">Journal of Low Power Electronics and Applications</option> <option value="jmmp">Journal of Manufacturing and Materials Processing</option> <option value="jmse">Journal of Marine Science and Engineering</option> <option value="jmahp">Journal of Market Access & Health Policy</option> <option value="jmms">Journal of Mind and Medical Sciences</option> <option value="jmp">Journal of Molecular Pathology</option> <option value="jnt">Journal of Nanotheranostics</option> <option value="jne">Journal of Nuclear Engineering</option> <option value="ohbm">Journal of Otorhinolaryngology, Hearing and Balance Medicine</option> <option value="jop">Journal of Parks</option> <option value="jpm">Journal of Personalized Medicine</option> <option value="jpbi">Journal of Pharmaceutical and BioTech Industry</option> <option value="jor">Journal of Respiration</option> <option value="jrfm">Journal of Risk and Financial Management</option> <option value="jsan">Journal of Sensor and Actuator Networks</option> <option value="joma">Journal of the Oman Medical Association</option> <option value="jtaer">Journal of Theoretical and Applied Electronic Commerce Research</option> <option value="jvd">Journal of Vascular Diseases</option> <option value="jox">Journal of Xenobiotics</option> <option value="jzbg">Journal of Zoological and Botanical Gardens</option> <option value="journalmedia">Journalism and Media</option> <option value="kidneydial">Kidney and Dialysis</option> <option value="kinasesphosphatases">Kinases and Phosphatases</option> <option value="knowledge">Knowledge</option> <option value="labmed">LabMed</option> <option value="laboratories">Laboratories</option> <option value="land">Land</option> <option value="languages">Languages</option> <option value="laws">Laws</option> <option value="life">Life</option> <option value="limnolrev">Limnological Review</option> <option value="lipidology">Lipidology</option> <option value="liquids">Liquids</option> <option value="literature">Literature</option> <option value="livers">Livers</option> <option value="logics">Logics</option> <option value="logistics">Logistics</option> <option value="lubricants">Lubricants</option> <option value="lymphatics">Lymphatics</option> <option value="make">Machine Learning and Knowledge Extraction</option> <option value="machines">Machines</option> <option value="macromol">Macromol</option> <option value="magnetism">Magnetism</option> <option value="magnetochemistry">Magnetochemistry</option> <option value="marinedrugs">Marine Drugs</option> <option value="materials">Materials</option> <option value="materproc">Materials Proceedings</option> <option value="mca">Mathematical and Computational Applications</option> <option value="mathematics">Mathematics</option> <option value="medsci">Medical Sciences</option> <option value="msf">Medical Sciences Forum</option> <option value="medicina">Medicina</option> <option value="medicines">Medicines</option> <option value="membranes">Membranes</option> <option value="merits">Merits</option> <option value="metabolites">Metabolites</option> <option value="metals">Metals</option> <option value="meteorology">Meteorology</option> <option value="methane">Methane</option> <option value="mps">Methods and Protocols</option> <option value="metrics">Metrics</option> <option value="metrology">Metrology</option> <option value="micro">Micro</option> <option value="microbiolres">Microbiology Research</option> <option value="micromachines">Micromachines</option> <option value="microorganisms">Microorganisms</option> <option value="microplastics">Microplastics</option> <option value="microwave">Microwave</option> <option value="minerals">Minerals</option> <option value="mining">Mining</option> <option value="modelling">Modelling</option> <option value="mmphys">Modern Mathematical Physics</option> <option value="molbank">Molbank</option> <option value="molecules">Molecules</option> <option value="mti">Multimodal Technologies and Interaction</option> <option value="muscles">Muscles</option> <option value="nanoenergyadv">Nanoenergy Advances</option> <option value="nanomanufacturing">Nanomanufacturing</option> <option value="nanomaterials">Nanomaterials</option> <option value="ndt">NDT</option> <option value="network">Network</option> <option value="neuroglia">Neuroglia</option> <option value="neurolint">Neurology International</option> <option value="neurosci">NeuroSci</option> <option value="nitrogen">Nitrogen</option> <option value="ncrna">Non-Coding RNA</option> <option value="nursrep">Nursing Reports</option> <option value="nutraceuticals">Nutraceuticals</option> <option value="nutrients">Nutrients</option> <option value="obesities">Obesities</option> <option value="oceans">Oceans</option> <option value="onco">Onco</option> <option value="optics">Optics</option> <option value="oral">Oral</option> <option value="organics">Organics</option> <option value="organoids">Organoids</option> <option value="osteology">Osteology</option> <option value="oxygen">Oxygen</option> <option value="parasitologia">Parasitologia</option> <option value="particles">Particles</option> <option value="pathogens">Pathogens</option> <option value="pathophysiology">Pathophysiology</option> <option value="pediatrrep">Pediatric Reports</option> <option value="pets">Pets</option> <option value="pharmaceuticals">Pharmaceuticals</option> <option value="pharmaceutics">Pharmaceutics</option> <option value="pharmacoepidemiology">Pharmacoepidemiology</option> <option value="pharmacy">Pharmacy</option> <option value="philosophies">Philosophies</option> <option value="photochem">Photochem</option> <option value="photonics">Photonics</option> <option value="phycology">Phycology</option> <option value="physchem">Physchem</option> <option value="psf">Physical Sciences Forum</option> <option value="physics">Physics</option> <option value="physiologia">Physiologia</option> <option value="plants">Plants</option> <option value="plasma">Plasma</option> <option value="platforms">Platforms</option> <option value="pollutants">Pollutants</option> <option value="polymers">Polymers</option> <option value="polysaccharides">Polysaccharides</option> <option value="populations">Populations</option> <option value="poultry">Poultry</option> <option value="powders">Powders</option> <option value="proceedings">Proceedings</option> <option value="processes">Processes</option> <option value="prosthesis">Prosthesis</option> <option value="proteomes">Proteomes</option> <option value="psychiatryint">Psychiatry International</option> <option value="psychoactives">Psychoactives</option> <option value="psycholint">Psychology International</option> <option value="publications">Publications</option> <option value="qubs">Quantum Beam Science</option> <option value="quantumrep">Quantum Reports</option> <option value="quaternary">Quaternary</option> <option value="radiation">Radiation</option> <option value="reactions">Reactions</option> <option value="realestate">Real Estate</option> <option value="receptors">Receptors</option> <option value="recycling">Recycling</option> <option value="rsee">Regional Science and Environmental Economics</option> <option value="religions">Religions</option> <option value="remotesensing">Remote Sensing</option> <option value="reports">Reports</option> <option value="reprodmed">Reproductive Medicine</option> <option value="resources">Resources</option> <option value="rheumato">Rheumato</option> <option value="risks">Risks</option> <option value="robotics">Robotics</option> <option value="ruminants">Ruminants</option> <option value="safety">Safety</option> <option value="sci">Sci</option> <option value="scipharm">Scientia Pharmaceutica</option> <option value="sclerosis">Sclerosis</option> <option value="seeds">Seeds</option> <option value="sensors">Sensors</option> <option value="separations">Separations</option> <option value="sexes">Sexes</option> <option value="signals">Signals</option> <option value="sinusitis">Sinusitis</option> <option value="smartcities">Smart Cities</option> <option value="socsci">Social Sciences</option> <option value="siuj">Société Internationale d’Urologie Journal</option> <option value="societies">Societies</option> <option value="software">Software</option> <option value="soilsystems">Soil Systems</option> <option value="solar">Solar</option> <option value="solids">Solids</option> <option value="spectroscj">Spectroscopy Journal</option> <option value="sports">Sports</option> <option value="standards">Standards</option> <option value="stats">Stats</option> <option value="stresses">Stresses</option> <option value="surfaces">Surfaces</option> <option value="surgeries">Surgeries</option> <option value="std">Surgical Techniques Development</option> <option value="sustainability">Sustainability</option> <option value="suschem">Sustainable Chemistry</option> <option value="symmetry">Symmetry</option> <option value="synbio">SynBio</option> <option value="systems">Systems</option> <option value="targets">Targets</option> <option value="taxonomy">Taxonomy</option> <option value="technologies">Technologies</option> <option value="telecom">Telecom</option> <option value="textiles">Textiles</option> <option value="thalassrep">Thalassemia Reports</option> <option value="therapeutics">Therapeutics</option> <option value="thermo">Thermo</option> <option value="timespace">Time and Space</option> <option value="tomography">Tomography</option> <option value="tourismhosp">Tourism and Hospitality</option> <option value="toxics">Toxics</option> <option value="toxins">Toxins</option> <option value="transplantology">Transplantology</option> <option value="traumacare">Trauma Care</option> <option value="higheredu">Trends in Higher Education</option> <option value="tropicalmed">Tropical Medicine and Infectious Disease</option> <option value="universe">Universe</option> <option value="urbansci">Urban Science</option> <option value="uro">Uro</option> <option value="vaccines">Vaccines</option> <option value="vehicles">Vehicles</option> <option value="venereology">Venereology</option> <option value="vetsci">Veterinary Sciences</option> <option value="vibration">Vibration</option> <option value="virtualworlds">Virtual Worlds</option> <option value="viruses">Viruses</option> <option value="vision">Vision</option> <option value="waste">Waste</option> <option value="water">Water</option> <option value="wild">Wild</option> <option value="wind">Wind</option> <option value="women">Women</option> <option value="world">World</option> <option value="wevj">World Electric Vehicle Journal</option> <option value="youth">Youth</option> <option value="zoonoticdis">Zoonotic Diseases</option> </select> <input name="email" type="email" placeholder="Enter your email address..." required="required" /> <button class="genericCaptcha button button--dark UA_FooterNewsletterSubscribeButton" type="submit">Subscribe</button> </form> </div> </div> </div> <div id="footer-copyright"> <div class="row"> <div class="columns large-6 medium-6 small-12 text-left"> © 1996-2025 MDPI (Basel, Switzerland) unless otherwise stated </div> <div class="columns large-6 medium-6 small-12 small-text-left medium-text-right large-text-right"> <a data-dropdown="drop-view-disclaimer" aria-controls="drop-view-disclaimer" aria-expanded="false" data-options="align:top; is_hover:true; hover_timeout:2000;"> Disclaimer </a> <div id="drop-view-disclaimer" class="f-dropdown label__btn__dropdown label__btn__dropdown--wide text-left" data-dropdown-content aria-hidden="true" tabindex="-1"> Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. </div> <a href="/about/terms-and-conditions"> Terms and Conditions </a> <a href="/about/privacy"> Privacy Policy </a> </div> </div> </div> </div> <div id="cookie-notification" class="js-allow-cookies" style="display: none;"> <div class="columns large-10 medium-10 small-12"> We use cookies on our website to ensure you get the best experience.<br class="show-for-medium-up"/> Read more about our cookies <a href="/about/privacy">here</a>. </div> <div class="columns large-2 medium-2 small-12 small-only-text-left text-right"> <a class="button button--default" href="/accept_cookies">Accept</a> </div> </div> </div> <div id="main-share-modal" class="reveal-modal reveal-modal-new reveal-modal-new--small" data-reveal aria-labelledby="modalTitle" aria-hidden="true" role="dialog"> <div class="row"> <div class="small-12 columns"> <h2 style="margin: 0;">Share Link</h2> </div> <div class="small-12 columns"> <div class="social-media-links UA_ShareModalLinks" style="text-align: left;"> <a href="/cdn-cgi/l/email-protection#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" title="Email"> <i class="fa fa-envelope-square" style="font-size: 30px;"></i> </a> <a href="https://twitter.com/intent/tweet?text=Investigating+the+Broad+Matrix-Gate+Network+in+the+Mitochondrial+ADP%2FATP+Carrier+through+Molecular+Dynamics+Simulations&hashtags=mdpimolecules&url=https%3A%2F%2Fwww.mdpi.com%2F1485542&via=Molecules_MDPI" onclick="windowOpen(this.href,600,800); return false" title="Twitter" target="_blank" rel="noopener noreferrer"> <i class="fa fa-twitter-x-square" style="font-size: 30px;"></i> </a> <a href=" http://www.linkedin.com/shareArticle?mini=true&url=https%3A%2F%2Fwww.mdpi.com%2F1485542&title=Investigating%20the%20Broad%20Matrix-Gate%20Network%20in%20the%20Mitochondrial%20ADP%2FATP%20Carrier%20through%20Molecular%20Dynamics%20Simulations%26source%3Dhttps%3A%2F%2Fwww.mdpi.com%26summary%3DThe%20mitochondrial%20ADP%2FATP%20carrier%20%28AAC%29%20exports%20ATP%20and%20imports%20ADP%20through%20alternating%20between%20cytosol-open%20%28c-%29%20and%20matrix-open%20%28m-%29%20states.%20The%20salt%20bridge%20networks%20near%20the%20matrix%20side%20%28m-gate%29%20and%20cytosol%20side%20%28c-gate%29%20are%20thought%20to%20be%20crucial%20%5B...%5D" onclick="windowOpen(this.href,600,800); return false" title="LinkedIn" target="_blank" rel="noopener noreferrer"> <i class="fa fa-linkedin-square" style="font-size: 30px;"></i> </a> <a href="https://www.facebook.com/sharer.php?u=https://www.mdpi.com/1485542" title="facebook" target="_blank" rel="noopener noreferrer"> <i class="fa fa-facebook-square" style="font-size: 30px;"></i> </a> <a href="javascript:void(0);" title="Wechat" data-reveal-id="weixin-share-modal"> <i class="fa fa-weixin-square" style="font-size: 26px;"></i> </a> <a href="http://www.reddit.com/submit?url=https://www.mdpi.com/1485542" title="Reddit" target="_blank" rel="noopener noreferrer"> <i class="fa fa-reddit-square" style="font-size: 30px;"></i> </a> <a href="http://www.mendeley.com/import/?url=https://www.mdpi.com/1485542" title="Mendeley" target="_blank" rel="noopener noreferrer"> <i class="fa fa-mendeley-square" style="font-size: 30px;"></i> </a> <a href="http://www.citeulike.org/posturl?url=https://www.mdpi.com/1485542" title="CiteULike" target="_blank" rel="noopener noreferrer"> <i class="fa fa-citeulike-square" style="font-size: 30px;"></i> </a> </div> </div> <div class="small-9 columns"> <input id="js-clipboard-text" type="text" readonly value="https://www.mdpi.com/1485542" /> </div> <div class="small-3 columns text-left"> <a class="button button--color js-clipboard-copy" data-clipboard-target="#js-clipboard-text">Copy</a> </div> </div> <a class="close-reveal-modal" aria-label="Close"> <i class="material-icons">clear</i> </a> </div> <div id="weixin-share-modal" class="reveal-modal reveal-modal-new" data-reveal aria-labelledby="weixin-share-modal-title" aria-hidden="true" role="dialog"> <div class="row"> <div class="small-12 columns"> <h2 id="weixin-share-modal-title" style="margin: 0;">Share</h2> </div> <div class="small-12 columns"> <div class="weixin-qr-code-section"> <?xml version="1.0" standalone="no"?> <!DOCTYPE svg PUBLIC "-//W3C//DTD SVG 1.1//EN" "http://www.w3.org/Graphics/SVG/1.1/DTD/svg11.dtd"> <svg width="300" height="300" version="1.1" xmlns="http://www.w3.org/2000/svg"> <desc>https://www.mdpi.com/1485542</desc> <g id="elements" fill="black" stroke="none"> <rect x="0" y="0" width="12" height="12" /> <rect x="12" y="0" width="12" height="12" /> <rect x="24" y="0" width="12" height="12" /> <rect x="36" y="0" width="12" height="12" /> <rect x="48" y="0" width="12" height="12" /> <rect x="60" y="0" width="12" height="12" /> <rect x="72" y="0" width="12" height="12" /> <rect x="108" y="0" width="12" height="12" /> <rect x="120" y="0" width="12" height="12" /> <rect x="132" y="0" width="12" height="12" /> <rect x="156" y="0" width="12" height="12" /> <rect x="168" y="0" width="12" height="12" /> <rect x="216" y="0" width="12" height="12" /> <rect x="228" y="0" width="12" height="12" /> <rect x="240" y="0" width="12" height="12" /> <rect x="252" y="0" width="12" height="12" /> <rect x="264" y="0" width="12" height="12" /> <rect x="276" y="0" width="12" height="12" /> <rect x="288" y="0" width="12" height="12" /> <rect x="0" y="12" width="12" height="12" /> <rect x="72" y="12" width="12" height="12" /> <rect x="132" y="12" width="12" height="12" /> <rect x="144" y="12" width="12" height="12" /> <rect x="156" y="12" width="12" height="12" /> <rect x="216" y="12" width="12" height="12" /> <rect x="288" y="12" width="12" height="12" /> <rect x="0" y="24" width="12" height="12" /> <rect x="24" y="24" width="12" height="12" /> <rect x="36" y="24" width="12" height="12" /> <rect x="48" y="24" width="12" height="12" /> <rect x="72" y="24" width="12" height="12" /> <rect x="108" y="24" width="12" height="12" /> <rect x="120" y="24" width="12" height="12" /> <rect x="132" y="24" width="12" height="12" /> <rect x="168" y="24" width="12" height="12" /> <rect x="192" y="24" width="12" height="12" /> <rect x="216" y="24" width="12" height="12" /> <rect x="240" y="24" width="12" height="12" /> <rect x="252" y="24" width="12" height="12" /> <rect x="264" y="24" width="12" height="12" /> <rect x="288" y="24" width="12" height="12" /> <rect x="0" y="36" width="12" height="12" /> <rect x="24" y="36" width="12" height="12" /> <rect x="36" y="36" width="12" height="12" /> <rect x="48" y="36" width="12" height="12" /> <rect x="72" y="36" width="12" height="12" /> <rect x="96" y="36" width="12" height="12" /> <rect x="120" y="36" width="12" height="12" /> <rect x="132" y="36" width="12" height="12" /> <rect x="144" y="36" width="12" height="12" /> <rect x="156" y="36" width="12" height="12" /> <rect x="180" y="36" width="12" height="12" /> <rect x="192" y="36" width="12" height="12" /> <rect x="216" y="36" width="12" height="12" /> <rect x="240" y="36" width="12" height="12" /> <rect x="252" y="36" width="12" height="12" /> <rect x="264" y="36" width="12" height="12" /> <rect x="288" y="36" width="12" height="12" /> <rect x="0" y="48" width="12" height="12" /> <rect x="24" y="48" width="12" height="12" /> <rect x="36" y="48" width="12" height="12" /> <rect x="48" y="48" width="12" height="12" /> <rect x="72" y="48" width="12" height="12" /> <rect x="96" y="48" width="12" height="12" /> <rect x="120" y="48" width="12" height="12" /> <rect x="144" y="48" width="12" height="12" /> <rect x="156" y="48" width="12" height="12" /> <rect x="216" y="48" width="12" height="12" /> <rect x="240" y="48" width="12" height="12" /> <rect x="252" y="48" width="12" height="12" /> <rect x="264" y="48" width="12" height="12" /> <rect x="288" y="48" width="12" height="12" /> <rect x="0" y="60" width="12" height="12" /> <rect x="72" y="60" width="12" height="12" /> <rect x="108" y="60" width="12" height="12" /> <rect x="120" y="60" width="12" height="12" /> <rect x="144" y="60" width="12" height="12" /> <rect x="156" y="60" width="12" height="12" /> <rect x="168" y="60" width="12" height="12" /> <rect x="192" y="60" width="12" height="12" /> <rect x="216" y="60" width="12" height="12" /> <rect x="288" y="60" width="12" height="12" /> <rect x="0" y="72" width="12" height="12" /> <rect x="12" y="72" width="12" height="12" /> <rect x="24" y="72" width="12" height="12" /> <rect x="36" y="72" width="12" height="12" /> <rect x="48" y="72" width="12" height="12" /> <rect x="60" y="72" width="12" height="12" /> <rect x="72" y="72" width="12" height="12" /> <rect x="96" y="72" width="12" height="12" /> <rect x="120" y="72" width="12" height="12" /> <rect x="144" y="72" width="12" height="12" /> <rect x="168" y="72" width="12" height="12" /> <rect x="192" y="72" width="12" height="12" /> <rect x="216" y="72" width="12" height="12" /> <rect x="228" y="72" width="12" height="12" /> <rect x="240" y="72" width="12" height="12" /> <rect x="252" y="72" width="12" height="12" /> <rect x="264" y="72" width="12" height="12" /> <rect x="276" y="72" width="12" height="12" /> <rect x="288" y="72" width="12" height="12" /> <rect x="108" y="84" width="12" height="12" /> <rect x="144" y="84" width="12" height="12" /> <rect x="168" y="84" width="12" height="12" /> <rect x="0" y="96" width="12" height="12" /> <rect x="12" y="96" width="12" height="12" /> <rect x="60" y="96" width="12" height="12" /> <rect x="72" y="96" width="12" height="12" /> <rect x="84" y="96" width="12" height="12" /> <rect x="108" y="96" width="12" height="12" /> <rect x="120" y="96" width="12" height="12" /> <rect x="144" y="96" width="12" height="12" /> <rect x="156" y="96" width="12" height="12" /> <rect x="168" y="96" width="12" height="12" /> <rect x="240" y="96" width="12" height="12" /> <rect x="252" y="96" width="12" height="12" /> <rect x="24" y="108" width="12" height="12" /> <rect x="48" y="108" width="12" height="12" /> <rect x="60" y="108" width="12" height="12" /> <rect x="84" y="108" width="12" height="12" /> <rect x="96" y="108" width="12" height="12" /> <rect x="120" y="108" width="12" height="12" /> <rect x="144" y="108" width="12" height="12" /> <rect x="156" y="108" width="12" height="12" /> <rect x="168" y="108" width="12" height="12" /> <rect x="180" y="108" width="12" height="12" /> <rect x="204" y="108" width="12" height="12" /> <rect x="228" y="108" width="12" height="12" /> <rect x="240" y="108" width="12" height="12" /> <rect x="252" y="108" width="12" height="12" /> <rect x="264" y="108" width="12" height="12" /> <rect x="276" y="108" width="12" height="12" /> <rect x="24" y="120" width="12" height="12" /> <rect x="36" y="120" width="12" height="12" /> <rect x="72" y="120" width="12" height="12" /> <rect x="96" y="120" width="12" height="12" /> <rect x="108" y="120" width="12" height="12" /> <rect x="168" y="120" width="12" height="12" /> <rect x="180" y="120" width="12" height="12" /> <rect x="204" y="120" width="12" height="12" /> <rect x="216" y="120" width="12" height="12" /> <rect x="228" y="120" width="12" height="12" /> <rect x="240" y="120" width="12" height="12" /> <rect x="252" y="120" width="12" height="12" /> <rect x="276" y="120" width="12" height="12" /> <rect x="288" y="120" width="12" height="12" /> <rect x="0" y="132" width="12" height="12" /> <rect x="24" y="132" width="12" height="12" /> <rect x="36" y="132" width="12" height="12" /> <rect x="48" y="132" width="12" height="12" /> <rect x="60" y="132" width="12" height="12" /> <rect x="120" y="132" width="12" height="12" /> <rect x="132" y="132" width="12" height="12" /> <rect x="144" y="132" width="12" height="12" /> <rect x="168" y="132" width="12" height="12" /> <rect x="204" y="132" width="12" height="12" /> <rect x="228" y="132" width="12" height="12" /> <rect x="252" y="132" width="12" height="12" /> <rect x="288" y="132" width="12" height="12" /> <rect x="0" y="144" width="12" height="12" /> <rect x="24" y="144" width="12" height="12" /> <rect x="36" y="144" width="12" height="12" /> <rect x="48" y="144" width="12" height="12" /> <rect x="72" y="144" width="12" height="12" /> <rect x="84" y="144" width="12" height="12" /> <rect x="108" y="144" width="12" height="12" /> <rect x="120" y="144" width="12" height="12" /> <rect x="168" y="144" width="12" height="12" /> <rect x="180" y="144" width="12" height="12" /> <rect x="216" y="144" width="12" height="12" /> <rect x="288" y="144" width="12" height="12" /> <rect x="0" y="156" width="12" height="12" /> <rect x="12" y="156" width="12" height="12" /> <rect x="84" y="156" width="12" height="12" /> <rect x="96" y="156" width="12" height="12" /> <rect x="108" y="156" width="12" height="12" /> <rect x="120" y="156" width="12" height="12" /> <rect x="180" y="156" width="12" height="12" /> <rect x="192" y="156" width="12" height="12" /> <rect x="204" y="156" width="12" height="12" /> <rect x="228" y="156" width="12" height="12" /> <rect x="276" y="156" width="12" height="12" /> <rect x="0" y="168" width="12" height="12" /> <rect x="24" y="168" width="12" height="12" /> <rect x="60" y="168" width="12" height="12" /> <rect x="72" y="168" width="12" height="12" /> <rect x="84" y="168" width="12" height="12" /> <rect x="144" y="168" width="12" height="12" /> <rect x="180" y="168" width="12" height="12" /> <rect x="204" y="168" width="12" height="12" /> <rect x="216" y="168" width="12" height="12" /> <rect x="228" y="168" width="12" height="12" /> <rect x="240" y="168" width="12" height="12" /> <rect x="252" y="168" width="12" height="12" /> <rect x="276" y="168" width="12" height="12" /> <rect x="288" y="168" width="12" height="12" /> <rect x="0" y="180" width="12" height="12" /> <rect x="24" y="180" width="12" height="12" /> <rect x="96" y="180" width="12" height="12" /> <rect x="108" y="180" width="12" height="12" /> <rect x="120" y="180" width="12" height="12" /> <rect x="144" y="180" width="12" height="12" /> <rect x="168" y="180" width="12" height="12" /> <rect x="204" y="180" width="12" height="12" /> <rect x="228" y="180" width="12" height="12" /> <rect x="252" y="180" width="12" height="12" /> <rect x="264" y="180" width="12" height="12" /> <rect x="288" y="180" width="12" height="12" /> <rect x="0" y="192" width="12" height="12" /> <rect x="24" y="192" width="12" height="12" /> <rect x="36" y="192" width="12" height="12" /> <rect x="48" y="192" width="12" height="12" /> <rect x="60" y="192" width="12" height="12" /> <rect x="72" y="192" width="12" height="12" /> <rect x="84" y="192" width="12" height="12" /> <rect x="108" y="192" width="12" height="12" /> <rect x="132" y="192" width="12" height="12" /> <rect x="168" y="192" width="12" height="12" /> <rect x="180" y="192" width="12" height="12" /> <rect x="192" y="192" width="12" height="12" /> <rect x="204" y="192" width="12" height="12" /> <rect x="216" y="192" width="12" height="12" /> <rect x="228" y="192" width="12" height="12" /> <rect x="240" y="192" width="12" height="12" /> <rect x="264" y="192" width="12" height="12" /> <rect x="96" y="204" width="12" height="12" /> <rect x="108" y="204" width="12" height="12" /> <rect x="120" y="204" width="12" height="12" /> <rect x="144" y="204" width="12" height="12" /> <rect x="192" y="204" width="12" height="12" /> <rect x="240" y="204" width="12" height="12" /> <rect x="0" y="216" width="12" height="12" /> <rect x="12" y="216" width="12" height="12" /> <rect x="24" y="216" width="12" height="12" /> <rect x="36" y="216" width="12" height="12" /> <rect x="48" y="216" width="12" height="12" /> <rect x="60" y="216" width="12" height="12" /> <rect x="72" y="216" width="12" height="12" /> <rect x="96" y="216" width="12" height="12" /> <rect x="108" y="216" width="12" height="12" /> <rect x="192" y="216" width="12" height="12" /> <rect x="216" y="216" width="12" height="12" /> <rect x="240" y="216" width="12" height="12" /> <rect x="288" y="216" width="12" height="12" /> <rect x="0" y="228" width="12" height="12" /> <rect x="72" y="228" width="12" height="12" /> <rect x="96" y="228" width="12" height="12" /> <rect x="108" y="228" width="12" height="12" /> <rect x="120" y="228" width="12" height="12" /> <rect x="132" y="228" width="12" height="12" /> <rect x="144" y="228" width="12" height="12" /> <rect x="156" y="228" width="12" height="12" /> <rect x="168" y="228" width="12" height="12" /> <rect x="180" y="228" width="12" height="12" /> <rect x="192" y="228" width="12" height="12" /> <rect x="240" y="228" width="12" height="12" /> <rect x="288" y="228" width="12" height="12" /> <rect x="0" y="240" width="12" height="12" /> <rect x="24" y="240" width="12" height="12" /> <rect x="36" y="240" width="12" height="12" /> <rect x="48" y="240" width="12" height="12" /> <rect x="72" y="240" width="12" height="12" /> <rect x="108" y="240" width="12" height="12" /> <rect x="144" y="240" width="12" height="12" /> <rect x="180" y="240" width="12" height="12" /> <rect x="192" y="240" width="12" height="12" /> <rect x="204" y="240" width="12" height="12" /> <rect x="216" y="240" width="12" height="12" /> <rect x="228" y="240" width="12" height="12" /> <rect x="240" y="240" width="12" height="12" /> <rect x="264" y="240" width="12" height="12" /> <rect x="276" y="240" width="12" height="12" /> <rect x="288" y="240" width="12" height="12" /> <rect x="0" y="252" width="12" height="12" /> <rect x="24" y="252" width="12" height="12" /> <rect x="36" y="252" width="12" height="12" /> <rect x="48" y="252" width="12" height="12" /> <rect x="72" y="252" width="12" height="12" /> <rect x="108" y="252" width="12" height="12" /> <rect x="120" y="252" width="12" height="12" /> <rect x="144" y="252" width="12" height="12" /> <rect x="180" y="252" width="12" height="12" /> <rect x="192" y="252" width="12" height="12" /> <rect x="216" y="252" width="12" height="12" /> <rect x="276" y="252" width="12" height="12" /> <rect x="288" y="252" width="12" height="12" /> <rect x="0" y="264" width="12" height="12" /> <rect x="24" y="264" width="12" height="12" /> <rect x="36" y="264" width="12" height="12" /> <rect x="48" y="264" width="12" height="12" /> <rect x="72" y="264" width="12" height="12" /> <rect x="108" y="264" width="12" height="12" /> <rect x="132" y="264" width="12" height="12" /> <rect x="192" y="264" width="12" height="12" /> <rect x="252" y="264" width="12" height="12" /> <rect x="264" y="264" width="12" height="12" /> <rect x="288" y="264" width="12" height="12" /> <rect x="0" y="276" width="12" height="12" /> <rect x="72" y="276" width="12" height="12" /> <rect x="96" y="276" width="12" height="12" /> <rect x="120" y="276" width="12" height="12" /> <rect x="132" y="276" width="12" height="12" /> <rect x="192" y="276" width="12" height="12" /> <rect x="204" y="276" width="12" height="12" /> <rect x="228" y="276" width="12" height="12" /> <rect x="240" y="276" width="12" height="12" /> <rect x="288" y="276" width="12" height="12" /> <rect x="0" y="288" width="12" height="12" /> <rect x="12" y="288" width="12" height="12" /> <rect x="24" y="288" width="12" height="12" /> <rect x="36" y="288" width="12" height="12" /> <rect x="48" y="288" width="12" height="12" /> <rect x="60" y="288" width="12" height="12" /> <rect x="72" y="288" width="12" height="12" /> <rect x="96" y="288" width="12" height="12" /> <rect x="108" y="288" width="12" height="12" /> <rect x="132" y="288" width="12" height="12" /> <rect x="156" y="288" width="12" height="12" /> <rect x="168" y="288" width="12" height="12" /> <rect x="192" y="288" width="12" height="12" /> <rect x="204" y="288" width="12" height="12" /> <rect x="252" y="288" width="12" height="12" /> <rect x="288" y="288" width="12" height="12" /> </g> </svg> </div> </div> </div> <a class="close-reveal-modal" aria-label="Close"> <i class="material-icons">clear</i> </a> </div> <a href="#" class="back-to-top"><span class="show-for-medium-up">Back to Top</span><span class="show-for-small">Top</span></a> <script data-cfasync="false" src="/cdn-cgi/scripts/5c5dd728/cloudflare-static/email-decode.min.js"></script><script src="https://pub.mdpi-res.com/assets/js/modernizr-2.8.3.min.js?5227e0738f7f421d?1739526160"></script> <script src="https://pub.mdpi-res.com/assets/js/jquery-1.12.4.min.js?4f252523d4af0b47?1739526160"></script> <script src="https://pub.mdpi-res.com/assets/js/foundation-5.5.3.min.js?6b2ec41c18b29054?1739526160"></script> <script src="https://pub.mdpi-res.com/assets/js/foundation-5.5.3.equalizer.min.js?0f6c549b75ec554c?1739526160"></script> <script src="https://pub.mdpi-res.com/assets/js/jquery.multiselect.js?0edd3998731d1091?1739526160"></script> <script src="https://pub.mdpi-res.com/assets/js/jquery.cycle2.min.js?63413052928f97ee?1739526160"></script> <script> // old browser fix - this way the console log rows won't throw (silent) errors in browsers not supporting console log if (!window.console) window.console = {}; if (!window.console.log) window.console.log = function () { }; var currentJournalNameSystem = "molecules"; $(document).ready(function() { $('select.foundation-select').multiselect({ search: true, minHeight: 130, maxHeight: 130, }); $(document).foundation({ orbit: { timer_speed: 4000, }, reveal: { animation: 'fadeAndPop', animation_speed: 100, } }); $(".chosen-select").each(function(element) { var maxSelected = (undefined !== $(this).data('maxselectedoptions') ? $(this).data('maxselectedoptions') : 100); $(this).on('chosen:ready', function(event, data) { var select = $(data.chosen.form_field); if (select.attr('id') === 'journal-browser-volume') { $(data.chosen.dropdown).addClass('UI_JournalBrowser_Volume_Options'); } if (select.attr('id') === 'journal-browser-issue') { $(data.chosen.dropdown).addClass('UI_JournalBrowser_Issue_Options'); } }).chosen({ display_disabled_options: false, disable_search_threshold: 7, max_selected_options: maxSelected, width: "100%" }); }); $(".toEncode").each(function(e) { var oldHref = $(this).attr("href"); var newHref = oldHref.replace('.botdefense.please.enable.javascript.','@'); $(this).attr("href", newHref); if (!$(this).hasClass("emailCaptcha")) { $(this).html(newHref.replace('mailto:', '')); } $(this).removeClass("visibility-hidden"); }); $(document).on('opened.fndtn.reveal', '[data-reveal]', function() { $(document).foundation('equalizer', 'reflow'); }); // fix the images that have tag height / width defined // otherwise the default foundation styles overwrite the tag definitions $("img").each(function() { if ($(this).attr('width') != undefined || $(this).attr('height') != undefined) { $(this).addClass("img-fixed"); } }); $("#basic_search, #advanced_search").submit(function(e) { var searchArguments = false; $(this).find("input,select").not("#search,.search-button").each(function() { if (undefined === $(this).val() || "" === $(this).val()) { $(this).attr('name', null); } else { $(this).attr('name'); searchArguments = true; } }); if (!searchArguments) { window.location = $(this).attr('action'); return false; } }); $(".hide-show-desktop-option").click(function(e) { e.preventDefault(); var parentDiv = $(this).closest("div"); $.ajax({ url: $(this).attr('href'), success: function(msg) { parentDiv.removeClass().hide(); } }); }); $(".generic-toggleable-header").click(function(e) { $(this).toggleClass("active"); $(this).next(".generic-toggleable-content").toggleClass("active"); }); /* * handle whole row as a link if the row contains only one visible link */ $("table.new tr").hover(function() { if ($(this).find("td:visible a").length == 1) { $(this).addClass("single-link"); } }, function() { $(this).removeClass("single-link"); }); $("table.new:not(.table-of-tables)").on("click", "tr.single-link", function(e) { var target = $(e.target); if (!e.ctrlKey && !target.is("a")) { $(this).find("td:visible a")[0].click(); } }); $(document).on("click", ".custom-accordion-for-small-screen-link", function(e) { if ($(this).closest("#basic_search").length > 0) { if ($(".search-container__advanced").first().is(":visible")) { openAdvanced() } } if (Foundation.utils.is_small_only()) { if ($(this).hasClass("active")) { $(this).removeClass("active"); $(this).next(".custom-accordion-for-small-screen-content").addClass("show-for-medium-up"); } else { $(this).addClass("active"); $(this).next(".custom-accordion-for-small-screen-content").removeClass("show-for-medium-up"); $(document).foundation('orbit', 'reflow'); } } if (undefined !== $(this).data("callback")) { var customCallback = $(this).data("callback"); func = window[customCallback]; func(); } }); $(document).on("click", ".js-open-small-search", function(e) { e.preventDefault(); $(this).toggleClass("active").closest(".tab-bar").toggleClass("active"); $(".search-container").toggleClass("hide-for-small-down"); }); $(document).on("click", ".js-open-menu", function(e) { $(".search-container").addClass("hide-for-small-down"); }); $(window).on('resize', function() { recalculate_main_browser_position(); recalculate_responsive_moving_containers(); }); updateSearchLabelVisibilities(); recalculate_main_browser_position(); recalculate_responsive_moving_containers(); if (window.document.documentMode == 11) { $("<link/>", { rel: "stylesheet", type: "text/css", href: "https://fonts.googleapis.com/icon?family=Material+Icons"}).appendTo("head"); } }); function recalculate_main_browser_position() { if (Foundation.utils.is_small_only()) { if ($("#js-main-top-container").parent("#js-large-main-top-container").length > 0) { $("#js-main-top-container").appendTo($("#js-small-main-top-container")); } } else { if ($("#js-main-top-container").parent("#js-small-main-top-container").length > 0) { $("#js-main-top-container").appendTo($("#js-large-main-top-container")); } } } function recalculate_responsive_moving_containers() { $(".responsive-moving-container.large").each(function() { var previousParent = $(".responsive-moving-container.active[data-id='"+$(this).data("id")+"']"); var movingContent = previousParent.html(); if (Foundation.utils.is_small_only()) { var currentParent = $(".responsive-moving-container.small[data-id='"+$(this).data("id")+"']"); } else if (Foundation.utils.is_medium_only()) { var currentParent = $(".responsive-moving-container.medium[data-id='"+$(this).data("id")+"']"); } else { var currentParent = $(".responsive-moving-container.large[data-id='"+$(this).data("id")+"']"); } if (previousParent.attr("class") !== currentParent.attr("class")) { currentParent.html(movingContent); previousParent.html(); currentParent.addClass("active"); previousParent.removeClass("active"); } }); } // cookies allowed is checked from a) local storage and b) from server separately so that the footer bar doesn't // get included in the custom page caches function checkCookiesAllowed() { var cookiesEnabled = localStorage.getItem("mdpi_cookies_enabled"); if (null === cookiesEnabled) { $.ajax({ url: "/ajax_cookie_value/mdpi_cookies_accepted", success: function(data) { if (data.value) { localStorage.setItem("mdpi_cookies_enabled", true); checkDisplaySurvey(); } else { $(".js-allow-cookies").show(); } } }); } else { checkDisplaySurvey(); } } function checkDisplaySurvey() { } window.addEventListener('CookiebotOnAccept', function (e) { var CookieDate = new Date; if (Cookiebot.consent.preferences) { CookieDate.setFullYear(CookieDate.getFullYear() + 1); document.cookie = "mdpi_layout_type_v2=mobile; path=/; expires=" + CookieDate.toUTCString() + ";"; $(".js-toggle-desktop-layout-link").css("display", "inline-block"); } }, false); window.addEventListener('CookiebotOnDecline', function (e) { if (!Cookiebot.consent.preferences) { $(".js-toggle-desktop-layout-link").hide(); if ("" === "desktop") { window.location = "/toggle_desktop_layout_cookie"; } } }, false); var hash = $(location).attr('hash'); if ("#share" === hash) { if (1 === $("#main-share-modal").length) { $('#main-share-modal').foundation('reveal', 'open'); } } </script> <script src="https://pub.mdpi-res.com/assets/js/lib.js?b86ef680a60436c6?1739526160"></script> <script src="https://pub.mdpi-res.com/assets/js/mdpi.js?c267ce58392b15da?1739526160"></script> <script>var banners_url = 'https://serve.mdpi.com';</script> <script type='text/javascript' src='https://pub.mdpi-res.com/assets/js/ifvisible.min.js?c621d19ecb761212?1739526160'></script> <script src="https://pub.mdpi-res.com/assets/js/xmltohtml/affix.js?ac4ea55275297c15?1739526160"></script> <script src="https://pub.mdpi-res.com/assets/js/clipboard.min.js?3f3688138a1b9fc4?1739526160"></script> <script type="text/javascript"> $(document).ready(function() { var helpFunctions = $(".middle-column__help__fixed"); var leftColumnAffix = $(".left-column__fixed"); var middleColumn = $("#middle-column"); var clone = null; helpFunctions.affix({ offset: { top: function() { return middleColumn.offset().top - 8 - (Foundation.utils.is_medium_only() ? 30 : 0); }, bottom: function() { return $("#footer").innerHeight() + 74 + (Foundation.utils.is_medium_only() ? 0 : 0); } } }); if (leftColumnAffix.length > 0) { clone = leftColumnAffix.clone(); clone.addClass("left-column__fixed__affix"); clone.insertBefore(leftColumnAffix); clone.css('width', leftColumnAffix.outerWidth() + 50); clone.affix({ offset: { top: function() { return leftColumnAffix.offset().top - 30 - (Foundation.utils.is_medium_only() ? 50 : 0); }, bottom: function() { return $("#footer").innerHeight() + 92 + (Foundation.utils.is_medium_only() ? 0 : 0); } } }); } $(window).on("resize", function() { if (clone !== null) { clone.css('width', leftColumnAffix.outerWidth() + 50); } }); new ClipboardJS('.js-clipboard-copy'); }); </script> <script src="https://pub.mdpi-res.com/assets/js/jquery-ui-1.13.2.min.js?1e2047978946a1d2?1739526160"></script> <script src="https://pub.mdpi-res.com/assets/js/slick.min.js?d5a61c749e44e471?1739526160"></script> <script> $(document).ready(function() { $(".link-article-menu").click(function(e) { e.preventDefault(); $(this).find('span').toggle(); $(this).next("div").toggleClass("active"); }); $(".js-similarity-related-articles").click(function(e) { e.preventDefault(); if ('' !== $('#recommended-articles-modal').attr('data-url')) { $('#recommended-articles-modal').foundation('reveal', 'open', $('#recommended-articles-modal').attr('data-url')); } }); $.ajax({ url: "/article/742771/similarity-related/show-link", success: function(result) { if (result.show) { $('#recommended-articles-modal').attr('data-url', result.link); $('.js-article-similarity-container').show(); } } }); $("#recommended-articles-modal").on("click", ".ga-title-link-recommended-article", function(e) { var clickEventUrl = $(this).data("click-event-url"); if (typeof clickEventUrl !== "undefined") { fetch(clickEventUrl, { method: "GET", mode: "no-cors" }); } }); $(document).on('opened.fndtn.reveal', '[data-reveal]', function() { var modal = $(this); if (modal.attr('id') === "author-biographies-modal") { modal.find('.multiple-items').slick({ slidesToShow: 1, nextArrow: '<a class="slick-next" href="#"><i class="material-icons">chevron_right</i></a>', prevArrow: '<a class="slick-prev" href="#"><i class="material-icons">chevron_left</i></a>', slidesToScroll: 1, draggable: false, }); modal.find('.multiple-items').slick('refresh'); } }); }); </script> <script type="text/javascript"> if (-1 !== window.location.href.indexOf("?src=")) { window.history.replaceState({}, '', `${location.pathname}`); } $(document).ready(function() { var scifeedCounter = 0; var search = window.location.search; var mathjaxReady = false; // late image file loading $("img[data-lsrc]").each(function() { $(this).attr("src", $(this).data("lsrc")); }); // late mathjax initialization var head = document.getElementsByTagName("head")[0]; var script = document.createElement("script"); script.type = "text/x-mathjax-config"; script[(window.opera ? "innerHTML" : "text")] = "MathJax.Hub.processSectionDelay = 0;\n" + "MathJax.Hub.Config({\n" + " \"menuSettings\": {\n" + " CHTMLpreview: false\n" + " },\n" + " \"CHTML-preview\":{\n" + " disabled: true\n" + " },\n" + " \"HTML-CSS\": {\n" + " scale: 90,\n" + " availableFonts: [],\n" + " preferredFont: null,\n" + " preferredFonts: null,\n" + " webFont:\"Gyre-Pagella\",\n" + " imageFont:'TeX',\n" + " undefinedFamily:\"'Arial Unicode MS',serif\",\n" + " linebreaks: { automatic: false }\n" + " },\n" + " \"TeX\": {\n" + " extensions: ['noErrors.js'],\n" + " noErrors: {\n" + " inlineDelimiters: [\"\",\"\"],\n" + " multiLine: true,\n" + " style: {\n" + " 'font-size': '90%',\n" + " 'text-align': 'left',\n" + " 'color': 'black',\n" + " 'padding': '1px 3px',\n" + " 'border': '1px solid'\n" + " }\n" + " }\n" + " }\n" + "});\n" + "MathJax.Hub.Register.StartupHook('End', function() {\n" + " refreshMathjaxWidths();\n" + " mathjaxReady = true;\n" + "});\n" + "MathJax.Hub.Startup.signal.Interest(function (message) {\n" + " if (message == 'End') {\n" + " var hypoLink = document.getElementById('hypothesis_frame');\n" + " if (null !== hypoLink) {\n" + " hypoLink.setAttribute('src', 'https://commenting.mdpi.com/embed.js');\n" + " }\n" + " }\n" + "});"; head.appendChild(script); script = document.createElement("script"); script.type = "text/javascript"; script.src = "https://pub.mdpi-res.com/bundles/mathjax/MathJax.js?config=TeX-AMS-MML_HTMLorMML"; head.appendChild(script); // article version checker if (0 === search.indexOf('?type=check_update&version=')) { $.ajax({ url: "/1420-3049/27/3/1071" + "/versioncheck" + search, success: function(result) { $(".js-check-update-container").html(result); } }); } $('#feed_option').click(function() { // tracker if ($('#scifeed_clicked').length<1) { $(this).append('<span style="display:none" id="scifeed_clicked">done</span>'); } $('#feed_data').toggle('slide', { direction: 'up'}, '1000'); // slideToggle(700); OR toggle(700) $("#scifeed_error_msg").html('').hide(); $("#scifeed_notice_msg").html('').hide(); }); $('#feed_option').click(function(event) { setTimeout(function(){ var captchaSection = $("#captchaSection"); captchaSection.removeClass('ui-helper-hidden').find('input').prop('disabled', false); // var img = captchaSection.find('img'); // img.attr('src', img.data('url') + "?" + (new Date()).getTime()); // $(".captcha_reload").trigger("click"); var img = document.getElementById('gregwar_captcha_scifeed'); img.src = '/generate-captcha/gcb_captcha?n=' + (new Date()).getTime(); },800); }); $(document).on('click', '.split_feeds', function() { var name = $( this ).attr('name'); var flag = 1 - ($(this).is(":checked")*1); $('.split_feeds').each(function (index) { if ($( this ).attr('name') !== name) { $(this)[0].checked = flag; } }); }); $(document).on('click', '#scifeed_submit, #scifeed_submit1', function(event) { event.preventDefault(); $(".captcha_reload").trigger("click"); $("#scifeed_error_msg").html(""); $("#scifeed_error_msg").hide(); }); $(document).on('click', '.subscription_toggle', function(event) { if ($(this).val() === 'Create SciFeed' && $('#scifeed_hidden_flag').length>0) { event.preventDefault(); // alert('Here there would be a captcha because user is not logged in'); var captchaSection = $("#captchaSection"); if (captchaSection.hasClass('ui-helper-hidden')) { captchaSection.removeClass('ui-helper-hidden').find('input').prop('disabled', false); var img = captchaSection.find('img'); img.attr('src', img.data('url') + "?" + (new Date()).getTime()); $("#reloadCaptcha").trigger("click"); } } }); $(document).on('click', '.scifeed_msg', function(){ $(this).hide(); }); $(document).on('click', '.article-scilit-search', function(e) { e.preventDefault(); var data = $(".article-scilit-search-data").val(); var dataArray = data.split(';').map(function(keyword) { return "(\"" + keyword.trim() + "\")"; }); var searchQuery = dataArray.join(" OR "); var searchUrl = encodeURI("https://www.scilit.com/articles/search?q="+ searchQuery + "&advanced=1&highlight=1"); var win = window.open(searchUrl, '_blank'); if (win) { win.focus(); } else { window.location(searchUrl); } }); display_stats(); citedCount(); follow_goto(); // Select the node that will be observed for mutations const targetNodes = document.getElementsByClassName('hypothesis-count-container'); // Options for the observer (which mutations to observe) const config = { attributes: false, childList: true, subtree: false }; // Callback function to execute when mutations are observed const callback = function(mutationList, observer) { for(const mutation of mutationList) { if (mutation.type === 'childList') { let node = $(mutation.target); if (parseInt(node.html()) > 0) { node.show(); } } } }; // Create an observer instance linked to the callback function const observer = new MutationObserver(callback); // Start observing the target node for configured mutations for(const targetNode of targetNodes) { observer.observe(targetNode, config); } // Select the node that will be observed for mutations const mathjaxTargetNode = document.getElementById('middle-column'); // Callback function to execute when mutations are observed const mathjaxCallback = function(mutationList, observer) { if (mathjaxReady && typeof(MathJax) !== 'undefined') { refreshMathjaxWidths(); } }; // Create an observer instance linked to the callback function const mathjaxObserver = new ResizeObserver(mathjaxCallback); // Start observing the target node for configured mutations mathjaxObserver.observe(mathjaxTargetNode); }); /* END $(document).ready */ function refreshMathjaxWidths() { let width = ($('.html-body').width()*0.9) + "px"; $('.MathJax_Display').css('max-width', width); $('.MJXc-display').css('max-width', width); } function sendScifeedFrom(form) { if (!$('#scifeed_email').val().trim()) { // empty email alert('Please, provide an email for subscribe to this scifeed'); return false; } else if (!$('#captchaSection').hasClass('ui-helper-hidden') && !$('#captchaSection').find('input').val().trim()) { // empty captcha alert('Please, fill the captcha field.'); return false; } else if( ((($('#scifeed_form').find('input:checkbox:checked').length)-($('#split_feeds:checked').length))<1) || ($('#scifeed_kwd_txt').length < 0 && !$('#scifeed_kwd_txt').val().trim()) || ($('#scifeed_author_txt').length<0 &&!$('#scifeed_author_txt').val().trim()) ) { alert('You did not select anything to subscribe'); return false; } else if(($('#scifeed_form').find('input:checkbox:checked').length)-($('#split_feeds2:checked').length)<1){ alert("You did not select anything to subscribe"); return false; } else { var url = $('#scifeed_subscribe_url').html(); var formData = $(form).serializeArray(); $.post(url, formData).done(function (data) { if (JSON.parse(data)) { $('.scifeed_msg').hide(); var res = JSON.parse(data); var successFeeds = 0; var errorFeeds = 0; if (res) { $('.scifeed_msg').html(''); $.each(res, function (index, val) { if (val) { if (val.error) { errorFeeds++; $("#scifeed_error_msg").append(index+' - '+val.error+'<br>'); } if (val.notice) // for successful feed creation { successFeeds++; // $("#scifeed_notice_msg").append(index+' - '+val.notice+'<br>'); $("#scifeed_notice_msg").append('<li>'+index+'</li>'); } } }); if (successFeeds>0) { text = $('#scifeed_notice_msg').html(); text = 'The following feed'+(successFeeds>1?'s have':' has')+ ' been sucessfully created:<br><ul>'+ text + '</ul>' +($('#scifeed_hidden_flag').length>0 ? 'You are not logged in, so you probably need to validate '+ (successFeeds>1?'them':' it')+'.<br>' :'' ) +'Please check your email'+(successFeeds>1?'s':'')+' for more details.'; //(successFeeds>1?' for each of them':'')+'.<br>'; $("#scifeed_notice_msg").html(text); $("#scifeed_notice_msg").show(); } if (errorFeeds>0) { $("#scifeed_error_msg").show();; } } $("#feed_data").hide(); } }); } } function follow_goto() { var hashStr = location.hash.replace("#",""); if(typeof hashStr !== 'undefined') { if( hashStr == 'supplementary') { document.getElementById('suppl_id').scrollIntoView(); } if( hashStr == 'citedby') { document.getElementById('cited_id').scrollIntoView(); } } } function cited() { $("#framed_div").toggle('fast', function(){ if ($(this).css('display') != 'none') { var loaded = document.getElementById("loaded"); if(loaded.innerHTML == "No") { // Load Xref result var container = document.getElementById("framed_div"); // This replace the content container.innerHTML = "<img src=\"https://pub.mdpi-res.com/img/loading_circle.gif?9a82694213036313?1739526160\" height=\"20\" width=\"20\" alt=\"Processing...\" style=\"vertical-align:middle; margin-right:0.6em;\">"; var url = "/citedby/10.3390%252Fmolecules27031071/1"; $.post(url, function(result) { if (result.success) { container.innerHTML = result.view; } loaded.innerHTML = "Yes"; }); } } return true; // for not going at the beginning of the page... }) return true; // for not going at the beginning of the page... } function detect_device() { // Added by Bastien (18/08/2014): based on the http://detectmobilebrowsers.com/ detector var check = false; (function(a){if(/(android|bb\d+|meego).+mobile|avantgo|bada\/|blackberry|blazer|compal|elaine|fennec|hiptop|iemobile|ip(hone|od)|iris|kindle|lge |maemo|midp|mmp|mobile.+firefox|netfront|opera m(ob|in)i|palm( os)?|phone|p(ixi|re)\/|plucker|pocket|psp|series(4|6)0|symbian|treo|up\.(browser|link)|vodafone|wap|windows (ce|phone)|xda|xiino/i.test(a)||/1207|6310|6590|3gso|4thp|50[1-6]i|770s|802s|a wa|abac|ac(er|oo|s\-)|ai(ko|rn)|al(av|ca|co)|amoi|an(ex|ny|yw)|aptu|ar(ch|go)|as(te|us)|attw|au(di|\-m|r |s )|avan|be(ck|ll|nq)|bi(lb|rd)|bl(ac|az)|br(e|v)w|bumb|bw\-(n|u)|c55\/|capi|ccwa|cdm\-|cell|chtm|cldc|cmd\-|co(mp|nd)|craw|da(it|ll|ng)|dbte|dc\-s|devi|dica|dmob|do(c|p)o|ds(12|\-d)|el(49|ai)|em(l2|ul)|er(ic|k0)|esl8|ez([4-7]0|os|wa|ze)|fetc|fly(\-|_)|g1 u|g560|gene|gf\-5|g\-mo|go(\.w|od)|gr(ad|un)|haie|hcit|hd\-(m|p|t)|hei\-|hi(pt|ta)|hp( i|ip)|hs\-c|ht(c(\-| |_|a|g|p|s|t)|tp)|hu(aw|tc)|i\-(20|go|ma)|i230|iac( |\-|\/)|ibro|idea|ig01|ikom|im1k|inno|ipaq|iris|ja(t|v)a|jbro|jemu|jigs|kddi|keji|kgt( |\/)|klon|kpt |kwc\-|kyo(c|k)|le(no|xi)|lg( g|\/(k|l|u)|50|54|\-[a-w])|libw|lynx|m1\-w|m3ga|m50\/|ma(te|ui|xo)|mc(01|21|ca)|m\-cr|me(rc|ri)|mi(o8|oa|ts)|mmef|mo(01|02|bi|de|do|t(\-| |o|v)|zz)|mt(50|p1|v )|mwbp|mywa|n10[0-2]|n20[2-3]|n30(0|2)|n50(0|2|5)|n7(0(0|1)|10)|ne((c|m)\-|on|tf|wf|wg|wt)|nok(6|i)|nzph|o2im|op(ti|wv)|oran|owg1|p800|pan(a|d|t)|pdxg|pg(13|\-([1-8]|c))|phil|pire|pl(ay|uc)|pn\-2|po(ck|rt|se)|prox|psio|pt\-g|qa\-a|qc(07|12|21|32|60|\-[2-7]|i\-)|qtek|r380|r600|raks|rim9|ro(ve|zo)|s55\/|sa(ge|ma|mm|ms|ny|va)|sc(01|h\-|oo|p\-)|sdk\/|se(c(\-|0|1)|47|mc|nd|ri)|sgh\-|shar|sie(\-|m)|sk\-0|sl(45|id)|sm(al|ar|b3|it|t5)|so(ft|ny)|sp(01|h\-|v\-|v )|sy(01|mb)|t2(18|50)|t6(00|10|18)|ta(gt|lk)|tcl\-|tdg\-|tel(i|m)|tim\-|t\-mo|to(pl|sh)|ts(70|m\-|m3|m5)|tx\-9|up(\.b|g1|si)|utst|v400|v750|veri|vi(rg|te)|vk(40|5[0-3]|\-v)|vm40|voda|vulc|vx(52|53|60|61|70|80|81|83|85|98)|w3c(\-| )|webc|whit|wi(g |nc|nw)|wmlb|wonu|x700|yas\-|your|zeto|zte\-/i.test(a.substr(0,4)))check = true})(navigator.userAgent||navigator.vendor||window.opera); return check; } function display_stats(){ $("#article_stats_div").toggle(); return false; } /* * Cited By Scopus */ function citedCount(){ $("#framed_div_cited_count").toggle('fast', function(){ if ($(this).css('display') != 'none') { var loaded = document.getElementById("loaded_cite_count"); // to load only once the result! if(loaded.innerHTML == "No") { // Load Xref result var d = document.getElementById("framed_div_cited_count"); // This replace the content d.innerHTML = "<img src=\"https://pub.mdpi-res.com/img/loading_circle.gif?9a82694213036313?1739526160\" height=\"20\" width=\"20\" alt=\"Processing...\" style=\"vertical-align:middle; margin-right:0.6em;\">"; $.ajax({ method : "POST", url : "/cite-count/10.3390%252Fmolecules27031071", success : function(data) { if (data.succ) { d.innerHTML = data.view; loaded.innerHTML = "Yes"; follow_goto(); } } }); } } // end else return true; // for not going at the beginning of the page... }) return true; // for not going at the beginning of the page... } </script><script type="text/javascript" src="https://pub.mdpi-res.com/assets/js/third-party/highcharts/highcharts.js?bdd06f45e34c33df?1739526160"></script><script type="text/javascript" src="https://pub.mdpi-res.com/assets/js/third-party/highcharts/modules/exporting.js?944dc938d06de3a8?1739526160"></script><script type="text/javascript" defer="defer"> var advancedStatsData; var selectedStatsType = "abstract"; $(function(){ var countWrapper = $('#counts-wrapper'); $('#author_stats_id #type_links a').on('click', function(e) { e.preventDefault(); selectedStatsType = $(this).data('type'); $('#article_advanced_stats').vectorMap('set', 'values', advancedStatsData[selectedStatsType]); $('#advanced_stats_max').html(advancedStatsData[selectedStatsType].max); $('#type_links a').removeClass('active'); $(this).addClass('active'); }); $.get('/1420-3049/27/3/1071/stats', function (result) { if (!result.success) { return; } // process article metrics part in left column var viewNumber = countWrapper.find(".view-number"); viewNumber.html(result.metrics.views); viewNumber.parent().toggleClass("count-div--grey", result.metrics.views == 0); var downloadNumber = countWrapper.find(".download-number"); downloadNumber.html(result.metrics.downloads); downloadNumber.parent().toggleClass("count-div--grey", result.metrics.downloads == 0); var citationsNumber = countWrapper.find(".citations-number"); citationsNumber.html(result.metrics.citations); citationsNumber.parent().toggleClass("count-div--grey", result.metrics.citations == 0); if (result.metrics.views > 0 || result.metrics.downloads > 0 || result.metrics.citations > 0) { countWrapper.find("#js-counts-wrapper__views, #js-counts-wrapper__downloads").addClass("visible").show(); if (result.metrics.citations > 0) { countWrapper.find('.citations-number').html(result.metrics.citations).show(); countWrapper.find("#js-counts-wrapper__citations").addClass("visible").show(); } else { countWrapper.find("#js-counts-wrapper__citations").remove(); } $("[data-id='article-counters']").removeClass("hidden"); } if (result.metrics.altmetrics_score > 0) { $("#js-altmetrics-donut").show(); } // process view chart in main column var jsondata = result.chart; var series = new Array(); $.each(jsondata.elements, function(i, element) { var dataValues = new Array(); $.each(element.values, function(i, value) { dataValues.push(new Array(value.tip, value.value)); }); series[i] = {name: element.text, data:dataValues}; }); Highcharts.setOptions({ chart: { style: { fontFamily: 'Arial,sans-serif' } } }); $('#article_stats_swf').highcharts({ chart: { type: 'line', width: $("#tabs").width() //* 0.91 }, credits: { enabled: false }, exporting: { enabled: true }, title: { text: jsondata.title.text, x: -20 //center }, xAxis: { categories: jsondata.x_axis.labels.labels, offset: jsondata.x_axis.offset, labels:{ step: jsondata.x_axis.labels.steps, rotation: 30 } }, yAxis: { max: jsondata.y_axis.max, min: jsondata.y_axis.min, offset: jsondata.y_axis.offset, labels: { steps: jsondata.y_axis.steps }, title: { enabled: false } }, tooltip: { formatter: function (){ return this.key.replace("#val#", this.y); } }, legend: { align: 'top', itemDistance: 50 }, series: series }); }); $('#supplement_link').click(function() { document.getElementById('suppl_id').scrollIntoView(); }); $('#stats_link').click(function() { document.getElementById('stats_id').scrollIntoView(); }); // open mol viewer for molbank special supplementary files $('.showJmol').click(function(e) { e.preventDefault(); var jmolModal = $("#jmolModal"); var url = "/article/742771/jsmol_viewer/__supplementary_id__"; url = url.replace(/__supplementary_id__/g, $(this).data('index')); $('#jsmol-content').attr('src', url); jmolModal.find(".content").html($(this).data('description')); jmolModal.foundation("reveal", "open"); }); }); !function() { "use strict"; function e(e) { try { if ("undefined" == typeof console) return; "error"in console ? console.error(e) : console.log(e) } catch (e) {} } function t(e) { return d.innerHTML = '<a href="' + e.replace(/"/g, """) + '"></a>', d.childNodes[0].getAttribute("href") || "" } function n(n, c) { var o = ""; var k = parseInt(n.substr(c + 4, 2), 16); for (var i = c; i < n.length; i += 2) { if (i != c + 4) { var s = parseInt(n.substr(i, 2), 16) ^ k; o += String.fromCharCode(s); } } try { o = decodeURIComponent(escape(o)); } catch (error) { console.error(error); } return t(o); } function c(t) { for (var r = t.querySelectorAll("a"), c = 0; c < r.length; c++) try { var o = r[c] , a = o.href.indexOf(l); a > -1 && (o.href = "mailto:" + n(o.href, a + l.length)) } catch (i) { e(i) } } function o(t) { for (var r = t.querySelectorAll(u), c = 0; c < r.length; c++) try { var o = r[c] , a = o.parentNode , i = o.getAttribute(f); if (i) { var l = n(i, 0) , d = document.createTextNode(l); a.replaceChild(d, o) } } catch (h) { e(h) } } function a(t) { for (var r = t.querySelectorAll("template"), n = 0; n < r.length; n++) try { i(r[n].content) } catch (c) { e(c) } } function i(t) { try { c(t), o(t), a(t) } catch (r) { e(r) } } var l = "/cnd-cgi/l/email-protection#" , u = ".__cf_email__" , f = "data-cfemail" , d = document.createElement("div"); i(document), function() { var e = document.currentScript || document.scripts[document.scripts.length - 1]; e.parentNode.removeChild(e) }() }(); </script><script type="text/javascript"> function setCookie(cname, cvalue, ctime) { ctime = (typeof ctime === 'undefined') ? 10*365*24*60*60*1000 : ctime; // default => 10 years var d = new Date(); d.setTime(d.getTime() + ctime); // ==> 1 hour = 60*60*1000 var expires = "expires="+d.toUTCString(); document.cookie = cname + "=" + cvalue + "; " + expires +"; path=/"; } function getCookie(cname) { var name = cname + "="; var ca = document.cookie.split(';'); for(var i=0; i<ca.length; i++) { var c = ca[i]; while (c.charAt(0)==' ') c = c.substring(1); if (c.indexOf(name) == 0) return c.substring(name.length, c.length); } return ""; } </script><script type="text/javascript" src="https://d1bxh8uas1mnw7.cloudfront.net/assets/embed.js"></script><script> $(document).ready(function() { if ($("#js-similarity-related-data").length > 0) { $.ajax({ url: '/article/742771/similarity-related', success: function(response) { $("#js-similarity-related-data").html(response); $("#js-related-articles-menu").show(); $(document).foundation('tab', 'reflow'); MathJax.Hub.Queue(["Typeset", MathJax.Hub]); } }); } }); </script><link rel="stylesheet" href="https://pub.mdpi-res.com/assets/css/jquery-ui-1.10.4.custom.min.css?80647d88647bf347?1739526160"><link rel="stylesheet" href="https://pub.mdpi-res.com/assets/css/magnific-popup.min.css?04d343e036f8eecd?1739526160"><script type="text/javascript" src="https://pub.mdpi-res.com/assets/js/magnific-popup.min.js?2be3d9e7dc569146?1739526160"></script><script> $(function() { $(".js-show-more-academic-editors").on("click", function(e) { e.preventDefault(); $(this).hide(); $(".academic-editor-container").removeClass("hidden"); }); }); </script> <link rel="stylesheet" href="https://pub.mdpi-res.com/assets/css/vmap/jqvmap.min.css?126a06688aa11c13?1739526160"> <script src="https://pub.mdpi-res.com/assets/js/vmap/jquery.vmap.min.js?935f68d33bdd88a1?1739526160"></script> <script src="https://pub.mdpi-res.com/assets/js/vmap/jquery.vmap.world.js?16677403c0e1bef1?1739526160"></script> <script> function updateSlick() { $('.multiple-items').slick('setPosition'); } $(document).ready(function() { $('.multiple-items').slick({ slidesToShow: 1, nextArrow: '<a class="slick-next" href="#"><i class="material-icons">chevron_right</i></a>', prevArrow: '<a class="slick-prev" href="#"><i class="material-icons">chevron_left</i></a>', slidesToScroll: 1, responsive: [ { breakpoint: 1024, settings: { slidesToShow: 1, slidesToScroll: 1, } }, { breakpoint: 600, settings: { slidesToShow: 1, slidesToScroll: 1, } }, { breakpoint: 480, settings: { slidesToShow: 1, slidesToScroll: 1, } } ] }); $('.multiple-items').show(); $(document).on('click', '.reviewReportSelector', function(e) { let path = $(this).attr('data-path'); handleReviews(path, $(this)); }); $(document).on('click', '.viewReviewReports', function(e) { let versionOne = $('#versionTab_1'); if (!versionOne.hasClass('activeTab')) { let path = $(this).attr('data-path'); handleReviews(path, versionOne); } location.href = "#reviewReports"; }); $(document).on('click', '.reviewersResponse, .authorResponse', function(e) { let version = $(this).attr('data-version'); let targetVersion = $('#versionTab_' + version); if (!targetVersion.hasClass('activeTab')) { let path = targetVersion.attr('data-path'); handleReviews(path, targetVersion); } location.href = $(this).attr('data-link'); }); $(document).on('click', '.tab', function (e) { e.preventDefault(); $('.tab').removeClass('activeTab'); $(this).addClass('activeTab') $('.tab').each(function() { $(this).closest('.tab-title').removeClass('active'); }); $(this).closest('.tab-title').addClass('active') }); }); function handleReviews(path, target) { $.ajax({ url: path, context: this, success: function (data) { $('.activeTab').removeClass('activeTab'); target.addClass('activeTab'); $('#reviewSection').html(data.view); }, error: function (xhr, ajaxOptions, thrownError) { console.log(xhr.status); console.log(thrownError); } }); } </script> <script src="https://pub.mdpi-res.com/assets/js/xmltohtml/affix.js?v1?1739526160"></script> <script src="https://pub.mdpi-res.com/assets/js/xmltohtml/storage.js?e9b262d3a3476d25?1739526160"></script> <script src="https://pub.mdpi-res.com/assets/js/xmltohtml/jquery-scrollspy.js?09cbaec0dbb35a67?1739526160"></script> <script src="https://pub.mdpi-res.com/assets/js/xmltohtml/magnific-popup.js?4a09c18460afb26c?1739526160"></script> <script src="https://pub.mdpi-res.com/assets/js/xmltohtml/underscore.js?f893e294cde60c24?1739526160"></script> <script type="text/javascript"> $('document').ready(function(){ $("#left-column").addClass("show-for-large-up"); $("#middle-column").removeClass("medium-9").removeClass("left-bordered").addClass("medium-12"); $(window).on('resize scroll', function() { /* if ($('.button--drop-down').isInViewport($(".top-bar").outerHeight())) { */ if ($('.button--drop-down').isInViewport()) { $("#js-button-download").hide(); } else { $("#js-button-download").show(); } }); }); $(document).on('DOMNodeInserted', function(e) { var element = $(e.target); if (element.hasClass('menu') && element.hasClass('html-nav') ) { element.addClass("side-menu-ul"); } }); </script> <script src="https://pub.mdpi-res.com/assets/js/xmltohtml/articles.js?5118449d9ad8913a?1739526160"></script> <script> repositionOpenSideBar = function() { $('#left-column').addClass("show-for-large-up show-for-medium-up").show(); $('#middle-column').removeClass('large-12').removeClass('medium-12'); $('#middle-column').addClass('large-9'); } repositionCloseSideBar = function() { $('#left-column').removeClass("show-for-large-up show-for-medium-up").hide(); $('#middle-column').removeClass('large-9'); $('#middle-column').addClass('large-12').addClass('medium-12'); } </script>   <script type="text/plain" data-cookieconsent="marketing"> !function(e,t,n,s,u,a){e.twq||(s=e.twq=function(){s.exe?s.exe.apply(s,arguments):s.queue.push(arguments); },s.version='1.1',s.queue=[],u=t.createElement(n),u.async=!0,u.src='//static.ads-twitter.com/uwt.js', a=t.getElementsByTagName(n)[0],a.parentNode.insertBefore(u,a))}(window,document,'script'); // Insert Twitter Pixel ID and Standard Event data below twq('init','o2pip'); twq('track','PageView'); </script>  <script>(function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'9134204e6d68fd2f',t:'MTczOTc3Nzk5NC4wMDAwMDA='};var a=document.createElement('script');a.nonce='';a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();</script></body> </html>

CINXE.COM

Investigating the Broad Matrix-Gate Network in the Mitochondrial ADP/ATP Carrier through Molecular Dynamics Simulations