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class="vector-toc-text"> <span class="vector-toc-numb">2</span> <span>Underlying models of protein structure and function</span> </div> </a> <button aria-controls="toc-Underlying_models_of_protein_structure_and_function-sublist" class="cdx-button cdx-button--weight-quiet cdx-button--icon-only vector-toc-toggle"> <span class="vector-icon mw-ui-icon-wikimedia-expand"></span> <span>Toggle Underlying models of protein structure and function subsection</span> </button> <ul id="toc-Underlying_models_of_protein_structure_and_function-sublist" class="vector-toc-list"> <li id="toc-Target_structure" class="vector-toc-list-item vector-toc-level-2"> <a class="vector-toc-link" href="#Target_structure"> <div class="vector-toc-text"> <span class="vector-toc-numb">2.1</span> <span>Target structure</span> </div> </a> <ul id="toc-Target_structure-sublist" class="vector-toc-list"> </ul> </li> <li id="toc-Sequence_space" class="vector-toc-list-item vector-toc-level-2"> <a class="vector-toc-link" href="#Sequence_space"> <div class="vector-toc-text"> <span class="vector-toc-numb">2.2</span> <span>Sequence space</span> </div> </a> <ul id="toc-Sequence_space-sublist" class="vector-toc-list"> </ul> </li> <li id="toc-Structural_flexibility" class="vector-toc-list-item vector-toc-level-2"> <a class="vector-toc-link" href="#Structural_flexibility"> <div class="vector-toc-text"> <span class="vector-toc-numb">2.3</span> <span>Structural flexibility</span> </div> </a> <ul id="toc-Structural_flexibility-sublist" class="vector-toc-list"> </ul> </li> <li id="toc-Energy_function" class="vector-toc-list-item vector-toc-level-2"> <a class="vector-toc-link" href="#Energy_function"> <div class="vector-toc-text"> <span class="vector-toc-numb">2.4</span> <span>Energy function</span> </div> </a> <ul id="toc-Energy_function-sublist" class="vector-toc-list"> <li id="toc-Challenges_for_effective_design_energy_functions" class="vector-toc-list-item vector-toc-level-3"> <a class="vector-toc-link" href="#Challenges_for_effective_design_energy_functions"> <div class="vector-toc-text"> <span class="vector-toc-numb">2.4.1</span> <span>Challenges for effective design energy functions</span> </div> </a> <ul id="toc-Challenges_for_effective_design_energy_functions-sublist" class="vector-toc-list"> </ul> </li> </ul> </li> </ul> </li> <li id="toc-As_an_optimization_problem" class="vector-toc-list-item vector-toc-level-1"> <a class="vector-toc-link" href="#As_an_optimization_problem"> <div class="vector-toc-text"> <span class="vector-toc-numb">3</span> <span>As an optimization problem</span> </div> </a> <ul id="toc-As_an_optimization_problem-sublist" class="vector-toc-list"> </ul> </li> <li id="toc-Algorithms" class="vector-toc-list-item vector-toc-level-1"> <a class="vector-toc-link" href="#Algorithms"> <div class="vector-toc-text"> <span class="vector-toc-numb">4</span> <span>Algorithms</span> </div> </a> <button aria-controls="toc-Algorithms-sublist" class="cdx-button cdx-button--weight-quiet cdx-button--icon-only vector-toc-toggle"> <span class="vector-icon mw-ui-icon-wikimedia-expand"></span> <span>Toggle Algorithms subsection</span> </button> <ul id="toc-Algorithms-sublist" class="vector-toc-list"> <li id="toc-With_mathematical_guarantees" class="vector-toc-list-item vector-toc-level-2"> <a class="vector-toc-link" href="#With_mathematical_guarantees"> <div class="vector-toc-text"> <span class="vector-toc-numb">4.1</span> <span>With mathematical guarantees</span> </div> </a> <ul id="toc-With_mathematical_guarantees-sublist" class="vector-toc-list"> <li id="toc-Dead-end_elimination" class="vector-toc-list-item vector-toc-level-3"> <a class="vector-toc-link" href="#Dead-end_elimination"> <div class="vector-toc-text"> <span class="vector-toc-numb">4.1.1</span> <span>Dead-end elimination</span> </div> </a> <ul id="toc-Dead-end_elimination-sublist" class="vector-toc-list"> </ul> </li> <li id="toc-Branch_and_bound" class="vector-toc-list-item vector-toc-level-3"> <a class="vector-toc-link" href="#Branch_and_bound"> <div class="vector-toc-text"> <span class="vector-toc-numb">4.1.2</span> <span>Branch and bound</span> </div> </a> <ul id="toc-Branch_and_bound-sublist" class="vector-toc-list"> </ul> </li> <li id="toc-Integer_linear_programming" class="vector-toc-list-item vector-toc-level-3"> <a class="vector-toc-link" href="#Integer_linear_programming"> <div class="vector-toc-text"> <span class="vector-toc-numb">4.1.3</span> <span>Integer linear programming</span> </div> </a> <ul id="toc-Integer_linear_programming-sublist" class="vector-toc-list"> </ul> </li> <li id="toc-Message-passing_based_approximations_to_the_linear_programming_dual" class="vector-toc-list-item vector-toc-level-3"> <a class="vector-toc-link" href="#Message-passing_based_approximations_to_the_linear_programming_dual"> <div class="vector-toc-text"> <span class="vector-toc-numb">4.1.4</span> <span>Message-passing based approximations to the linear programming dual</span> </div> </a> <ul id="toc-Message-passing_based_approximations_to_the_linear_programming_dual-sublist" class="vector-toc-list"> </ul> </li> </ul> </li> <li id="toc-Optimization_algorithms_without_guarantees" class="vector-toc-list-item vector-toc-level-2"> <a class="vector-toc-link" href="#Optimization_algorithms_without_guarantees"> <div class="vector-toc-text"> <span class="vector-toc-numb">4.2</span> <span>Optimization algorithms without guarantees</span> </div> </a> <ul id="toc-Optimization_algorithms_without_guarantees-sublist" class="vector-toc-list"> <li id="toc-Monte_Carlo_and_simulated_annealing" class="vector-toc-list-item vector-toc-level-3"> <a class="vector-toc-link" href="#Monte_Carlo_and_simulated_annealing"> <div class="vector-toc-text"> <span class="vector-toc-numb">4.2.1</span> <span>Monte Carlo and simulated annealing</span> </div> </a> <ul id="toc-Monte_Carlo_and_simulated_annealing-sublist" class="vector-toc-list"> </ul> </li> <li id="toc-FASTER" class="vector-toc-list-item vector-toc-level-3"> <a class="vector-toc-link" href="#FASTER"> <div class="vector-toc-text"> <span class="vector-toc-numb">4.2.2</span> <span>FASTER</span> </div> </a> <ul id="toc-FASTER-sublist" class="vector-toc-list"> </ul> </li> <li id="toc-Belief_propagation" class="vector-toc-list-item vector-toc-level-3"> <a class="vector-toc-link" href="#Belief_propagation"> <div class="vector-toc-text"> <span class="vector-toc-numb">4.2.3</span> <span>Belief propagation</span> </div> </a> <ul id="toc-Belief_propagation-sublist" class="vector-toc-list"> </ul> </li> </ul> </li> </ul> </li> <li id="toc-Applications_and_examples_of_designed_proteins" class="vector-toc-list-item vector-toc-level-1"> <a class="vector-toc-link" href="#Applications_and_examples_of_designed_proteins"> <div class="vector-toc-text"> <span class="vector-toc-numb">5</span> <span>Applications and examples of designed proteins</span> </div> </a> <button aria-controls="toc-Applications_and_examples_of_designed_proteins-sublist" class="cdx-button cdx-button--weight-quiet cdx-button--icon-only vector-toc-toggle"> <span class="vector-icon mw-ui-icon-wikimedia-expand"></span> <span>Toggle Applications and examples of designed proteins subsection</span> </button> <ul id="toc-Applications_and_examples_of_designed_proteins-sublist" class="vector-toc-list"> <li id="toc-Enzyme_design" class="vector-toc-list-item vector-toc-level-2"> <a class="vector-toc-link" href="#Enzyme_design"> <div class="vector-toc-text"> <span class="vector-toc-numb">5.1</span> <span>Enzyme design</span> </div> </a> <ul id="toc-Enzyme_design-sublist" class="vector-toc-list"> </ul> </li> <li id="toc-Semi-rational_design" class="vector-toc-list-item vector-toc-level-2"> <a class="vector-toc-link" href="#Semi-rational_design"> <div class="vector-toc-text"> <span class="vector-toc-numb">5.2</span> <span>Semi-rational design</span> </div> </a> <ul id="toc-Semi-rational_design-sublist" class="vector-toc-list"> </ul> </li> <li id="toc-Design_for_affinity" class="vector-toc-list-item vector-toc-level-2"> <a class="vector-toc-link" href="#Design_for_affinity"> <div class="vector-toc-text"> <span class="vector-toc-numb">5.3</span> <span>Design for affinity</span> </div> </a> <ul id="toc-Design_for_affinity-sublist" class="vector-toc-list"> <li id="toc-Scoring_binding_predictions" class="vector-toc-list-item vector-toc-level-3"> <a class="vector-toc-link" href="#Scoring_binding_predictions"> <div class="vector-toc-text"> <span class="vector-toc-numb">5.3.1</span> <span>Scoring binding predictions</span> </div> </a> <ul id="toc-Scoring_binding_predictions-sublist" class="vector-toc-list"> </ul> </li> </ul> </li> <li id="toc-Design_for_specificity" class="vector-toc-list-item vector-toc-level-2"> <a class="vector-toc-link" href="#Design_for_specificity"> <div class="vector-toc-text"> <span class="vector-toc-numb">5.4</span> <span>Design for specificity</span> </div> </a> <ul id="toc-Design_for_specificity-sublist" class="vector-toc-list"> </ul> </li> <li id="toc-Protein_resurfacing" class="vector-toc-list-item vector-toc-level-2"> <a class="vector-toc-link" href="#Protein_resurfacing"> <div class="vector-toc-text"> <span class="vector-toc-numb">5.5</span> <span>Protein resurfacing</span> </div> </a> <ul id="toc-Protein_resurfacing-sublist" class="vector-toc-list"> </ul> </li> <li id="toc-Design_of_globular_proteins" class="vector-toc-list-item vector-toc-level-2"> <a class="vector-toc-link" href="#Design_of_globular_proteins"> <div class="vector-toc-text"> <span class="vector-toc-numb">5.6</span> <span>Design of globular proteins</span> </div> </a> <ul id="toc-Design_of_globular_proteins-sublist" class="vector-toc-list"> </ul> </li> <li id="toc-Design_of_membrane_proteins" class="vector-toc-list-item vector-toc-level-2"> <a class="vector-toc-link" href="#Design_of_membrane_proteins"> <div class="vector-toc-text"> <span class="vector-toc-numb">5.7</span> <span>Design of membrane proteins</span> </div> </a> <ul id="toc-Design_of_membrane_proteins-sublist" class="vector-toc-list"> </ul> </li> <li id="toc-Other_applications" class="vector-toc-list-item vector-toc-level-2"> <a class="vector-toc-link" href="#Other_applications"> <div class="vector-toc-text"> <span class="vector-toc-numb">5.8</span> <span>Other applications</span> </div> </a> <ul id="toc-Other_applications-sublist" class="vector-toc-list"> </ul> </li> </ul> </li> <li id="toc-See_also" class="vector-toc-list-item vector-toc-level-1"> <a class="vector-toc-link" href="#See_also"> <div class="vector-toc-text"> <span class="vector-toc-numb">6</span> <span>See also</span> </div> </a> <ul id="toc-See_also-sublist" class="vector-toc-list"> </ul> </li> <li id="toc-References" class="vector-toc-list-item vector-toc-level-1"> <a class="vector-toc-link" href="#References"> <div class="vector-toc-text"> <span class="vector-toc-numb">7</span> <span>References</span> </div> </a> <ul id="toc-References-sublist" class="vector-toc-list"> </ul> </li> <li id="toc-Further_reading" class="vector-toc-list-item vector-toc-level-1"> <a class="vector-toc-link" href="#Further_reading"> <div class="vector-toc-text"> <span class="vector-toc-numb">8</span> <span>Further reading</span> </div> </a> <ul id="toc-Further_reading-sublist" class="vector-toc-list"> </ul> </li> </ul> </div> </div> </nav> </div> </div> <div class="mw-content-container"> <main id="content" class="mw-body"> <header class="mw-body-header vector-page-titlebar"> <nav aria-label="Contents" class="vector-toc-landmark"> <div id="vector-page-titlebar-toc" class="vector-dropdown vector-page-titlebar-toc vector-button-flush-left" title="Table of Contents" > <input type="checkbox" id="vector-page-titlebar-toc-checkbox" role="button" aria-haspopup="true" data-event-name="ui.dropdown-vector-page-titlebar-toc" class="vector-dropdown-checkbox " aria-label="Toggle the table of 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interwiki-ca mw-list-item"><a href="https://ca.wikipedia.org/wiki/Disseny_de_prote%C3%AFnes" title="Disseny de proteïnes – Catalan" lang="ca" hreflang="ca" data-title="Disseny de proteïnes" data-language-autonym="Català" data-language-local-name="Catalan" class="interlanguage-link-target"><span>Català</span></a></li><li class="interlanguage-link interwiki-de mw-list-item"><a href="https://de.wikipedia.org/wiki/Proteindesign" title="Proteindesign – German" lang="de" hreflang="de" data-title="Proteindesign" data-language-autonym="Deutsch" data-language-local-name="German" class="interlanguage-link-target"><span>Deutsch</span></a></li><li class="interlanguage-link interwiki-fa mw-list-item"><a href="https://fa.wikipedia.org/wiki/%D8%B7%D8%B1%D8%A7%D8%AD%DB%8C_%D9%BE%D8%B1%D9%88%D8%AA%D8%A6%DB%8C%D9%86" title="طراحی پروتئین – Persian" lang="fa" hreflang="fa" data-title="طراحی پروتئین" data-language-autonym="فارسی" data-language-local-name="Persian" class="interlanguage-link-target"><span>فارسی</span></a></li><li class="interlanguage-link interwiki-ko mw-list-item"><a href="https://ko.wikipedia.org/wiki/%EB%8B%A8%EB%B0%B1%EC%A7%88_%EC%84%A4%EA%B3%84" title="단백질 설계 – Korean" lang="ko" hreflang="ko" data-title="단백질 설계" data-language-autonym="한국어" data-language-local-name="Korean" class="interlanguage-link-target"><span>한국어</span></a></li><li class="interlanguage-link interwiki-hr mw-list-item"><a href="https://hr.wikipedia.org/wiki/Bjelan%C4%8Devinsko_dizajniranje" title="Bjelančevinsko dizajniranje – Croatian" lang="hr" hreflang="hr" data-title="Bjelančevinsko dizajniranje" data-language-autonym="Hrvatski" data-language-local-name="Croatian" class="interlanguage-link-target"><span>Hrvatski</span></a></li><li class="interlanguage-link interwiki-it mw-list-item"><a href="https://it.wikipedia.org/wiki/Progettazione_di_proteine" title="Progettazione di proteine – Italian" lang="it" hreflang="it" data-title="Progettazione di proteine" 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<div class="vector-body-before-content"> <div class="mw-indicators"> </div> <div id="siteSub" class="noprint">From Wikipedia, the free encyclopedia</div> </div> <div id="contentSub"><div id="mw-content-subtitle"></div></div> <div id="mw-content-text" class="mw-body-content"><div class="mw-content-ltr mw-parser-output" lang="en" dir="ltr"><div class="shortdescription nomobile noexcerpt noprint searchaux" style="display:none">Rational design of new protein molecules</div> <style data-mw-deduplicate="TemplateStyles:r1236090951">.mw-parser-output .hatnote{font-style:italic}.mw-parser-output div.hatnote{padding-left:1.6em;margin-bottom:0.5em}.mw-parser-output .hatnote i{font-style:normal}.mw-parser-output .hatnote+link+.hatnote{margin-top:-0.5em}@media print{body.ns-0 .mw-parser-output .hatnote{display:none!important}}</style><div role="note" class="hatnote navigation-not-searchable">This article is about rational protein design. For the broader engineering of proteins, see <a href="/wiki/Protein_engineering" title="Protein engineering">Protein engineering</a>.</div> <p class="mw-empty-elt"> </p><p><b>Protein design</b> is the <a href="/wiki/Rational_design" title="Rational design">rational design</a> of new <a href="/wiki/Protein" title="Protein">protein</a> molecules to design novel activity, behavior, or purpose, and to advance basic understanding of protein function.<sup id="cite_ref-1" class="reference"><a href="#cite_note-1"><span class="cite-bracket">[</span>1<span class="cite-bracket">]</span></a></sup> Proteins can be designed from scratch (<i>de novo</i> design) or by making calculated variants of a known protein structure and its sequence (termed <i>protein redesign</i>). <b>Rational protein design</b> approaches make protein-sequence predictions that will fold to specific structures. These predicted sequences can then be validated experimentally through methods such as <a href="/wiki/Peptide_synthesis" title="Peptide synthesis">peptide synthesis</a>, <a href="/wiki/Site-directed_mutagenesis" title="Site-directed mutagenesis">site-directed mutagenesis</a>, or <a href="/wiki/Artificial_gene_synthesis" title="Artificial gene synthesis">artificial gene synthesis</a>. </p><p>Rational protein design dates back to the mid-1970s.<sup id="cite_ref-richardson1989_2-0" class="reference"><a href="#cite_note-richardson1989-2"><span class="cite-bracket">[</span>2<span class="cite-bracket">]</span></a></sup> Recently, however, there were numerous examples of successful rational design of water-soluble and even transmembrane peptides and proteins, in part due to a better understanding of different factors contributing to <a href="/wiki/Protein_folding" title="Protein folding">protein structure stability</a> and development of better computational methods. </p> <meta property="mw:PageProp/toc" /> <div class="mw-heading mw-heading2"><h2 id="Overview_and_history">Overview and history</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Protein_design&action=edit&section=1" title="Edit section: Overview and history"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>The goal in rational protein design is to predict <a href="/wiki/Amino_acid" title="Amino acid">amino acid</a> <a href="/wiki/Protein_primary_structure" title="Protein primary structure">sequences</a> that will <a href="/wiki/Protein_folding" title="Protein folding">fold</a> to a specific protein structure. Although the number of possible protein sequences is vast, growing exponentially with the size of the protein chain, only a subset of them will fold reliably and quickly to one <a href="/wiki/Native_state" title="Native state">native state</a>. Protein design involves identifying novel sequences within this subset. The native state of a protein is the conformational <a href="/wiki/Thermodynamic_free_energy" title="Thermodynamic free energy">free energy</a> minimum for the chain. Thus, protein design is the search for sequences that have the chosen structure as a free energy minimum. In a sense, it is the reverse of <a href="/wiki/Protein_structure_prediction" title="Protein structure prediction">protein structure prediction</a>. In design, a <a href="/wiki/Protein_tertiary_structure" title="Protein tertiary structure">tertiary structure</a> is specified, and a sequence that will fold to it is identified. Hence, it is also termed <i>inverse folding</i>. Protein design is then an optimization problem: using some scoring criteria, an optimized sequence that will fold to the desired structure is chosen. </p><p>When the first proteins were rationally designed during the 1970s and 1980s, the sequence for these was optimized manually based on analyses of other known proteins, the sequence composition, amino acid charges, and the geometry of the desired structure.<sup id="cite_ref-richardson1989_2-1" class="reference"><a href="#cite_note-richardson1989-2"><span class="cite-bracket">[</span>2<span class="cite-bracket">]</span></a></sup> The first designed proteins are attributed to Bernd Gutte, who designed a reduced version of a known catalyst, bovine ribonuclease, and tertiary structures consisting of beta-sheets and alpha-helices, including a binder of <a href="/wiki/DDT" title="DDT">DDT</a>. Urry and colleagues later designed <a href="/wiki/Elastin" title="Elastin">elastin</a>-like <a href="/wiki/Fibrous_protein" title="Fibrous protein">fibrous</a> peptides based on rules on sequence composition. Richardson and coworkers designed a 79-residue protein with no sequence homology to a known protein.<sup id="cite_ref-richardson1989_2-2" class="reference"><a href="#cite_note-richardson1989-2"><span class="cite-bracket">[</span>2<span class="cite-bracket">]</span></a></sup> In the 1990s, the advent of powerful computers, <a href="/wiki/Conformational_isomerism#Protein_rotamer_libraries" class="mw-redirect" title="Conformational isomerism">libraries of amino acid conformations</a>, and force fields developed mainly for <a href="/wiki/Molecular_dynamics" title="Molecular dynamics">molecular dynamics</a> simulations enabled the development of structure-based computational protein design tools. Following the development of these computational tools, great success has been achieved over the last 30 years in protein design. The first protein successfully designed completely <i>de novo</i> was done by <a href="/wiki/Stephen_Mayo" class="mw-redirect" title="Stephen Mayo">Stephen Mayo</a> and coworkers in 1997,<sup id="cite_ref-dahiyat1997_3-0" class="reference"><a href="#cite_note-dahiyat1997-3"><span class="cite-bracket">[</span>3<span class="cite-bracket">]</span></a></sup> and, shortly after, in 1999 <a href="/wiki/Peter_S._Kim" title="Peter S. Kim">Peter S. Kim</a> and coworkers designed dimers, trimers, and tetramers of unnatural right-handed <a href="/wiki/Coiled_coil" title="Coiled coil">coiled coils</a>.<sup id="cite_ref-gordon99review_4-0" class="reference"><a href="#cite_note-gordon99review-4"><span class="cite-bracket">[</span>4<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-harbury99_5-0" class="reference"><a href="#cite_note-harbury99-5"><span class="cite-bracket">[</span>5<span class="cite-bracket">]</span></a></sup> In 2003, <a href="/wiki/David_Baker_(biochemist)" title="David Baker (biochemist)">David Baker</a>'s laboratory designed a full protein to a fold never seen before in nature.<sup id="cite_ref-kuhlman03_6-0" class="reference"><a href="#cite_note-kuhlman03-6"><span class="cite-bracket">[</span>6<span class="cite-bracket">]</span></a></sup> Later, in 2008, Baker's group computationally designed enzymes for two different reactions.<sup id="cite_ref-7" class="reference"><a href="#cite_note-7"><span class="cite-bracket">[</span>7<span class="cite-bracket">]</span></a></sup> In 2010, one of the most powerful broadly neutralizing antibodies was isolated from patient serum using a computationally designed protein probe.<sup id="cite_ref-wu2010a_8-0" class="reference"><a href="#cite_note-wu2010a-8"><span class="cite-bracket">[</span>8<span class="cite-bracket">]</span></a></sup> Due to these and other successes (e.g., see <a href="#Applications_and_examples_of_designed_proteins">examples</a> below), protein design has become one of the most important tools available for <a href="/wiki/Protein_engineering" title="Protein engineering">protein engineering</a>. There is great hope that the design of new proteins, small and large, will have uses in <a href="/wiki/Biomedicine" title="Biomedicine">biomedicine</a> and <a href="/wiki/Bioengineering" class="mw-redirect" title="Bioengineering">bioengineering</a>. </p> <div class="mw-heading mw-heading2"><h2 id="Underlying_models_of_protein_structure_and_function">Underlying models of protein structure and function</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Protein_design&action=edit&section=2" title="Edit section: Underlying models of protein structure and function"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>Protein design programs use <a href="/wiki/Bioinformatics" title="Bioinformatics">computer models</a> of the molecular forces that drive proteins in <i><a href="/wiki/In_vivo" title="In vivo">in vivo</a></i> environments. In order to make the problem tractable, these forces are simplified by protein design models. Although protein design programs vary greatly, they have to address four main modeling questions: What is the target structure of the design, what flexibility is allowed on the target structure, which sequences are included in the search, and which force field will be used to score sequences and structures. </p> <div class="mw-heading mw-heading3"><h3 id="Target_structure">Target structure</h3><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Protein_design&action=edit&section=3" title="Edit section: Target structure"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <figure class="mw-default-size mw-halign-left" typeof="mw:File/Thumb"><a href="/wiki/File:Top7.png" class="mw-file-description"><img src="//upload.wikimedia.org/wikipedia/commons/thumb/a/a2/Top7.png/220px-Top7.png" decoding="async" width="220" height="220" class="mw-file-element" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/a/a2/Top7.png/330px-Top7.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/a/a2/Top7.png/440px-Top7.png 2x" data-file-width="800" data-file-height="800" /></a><figcaption>The <a href="/wiki/Top7" title="Top7">Top7</a> protein was one of the first proteins designed for a fold that had never been seen before in nature<sup id="cite_ref-kuhlman03_6-1" class="reference"><a href="#cite_note-kuhlman03-6"><span class="cite-bracket">[</span>6<span class="cite-bracket">]</span></a></sup></figcaption></figure> <p>Protein function is heavily dependent on protein structure, and rational protein design uses this relationship to design function by designing proteins that have a target structure or fold. Thus, by definition, in rational protein design the target structure or ensemble of structures must be known beforehand. This contrasts with other forms of protein engineering, such as <a href="/wiki/Directed_evolution" title="Directed evolution">directed evolution</a>, where a variety of methods are used to find proteins that achieve a specific function, and with <a href="/wiki/Protein_structure_prediction" title="Protein structure prediction">protein structure prediction</a> where the sequence is known, but the structure is unknown. </p><p>Most often, the target structure is based on a known structure of another protein. However, novel folds not seen in nature have been made increasingly possible. Peter S. Kim and coworkers designed trimers and tetramers of unnatural coiled coils, which had not been seen before in nature.<sup id="cite_ref-gordon99review_4-1" class="reference"><a href="#cite_note-gordon99review-4"><span class="cite-bracket">[</span>4<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-harbury99_5-1" class="reference"><a href="#cite_note-harbury99-5"><span class="cite-bracket">[</span>5<span class="cite-bracket">]</span></a></sup> The protein Top7, developed in <a href="/wiki/David_Baker_(biochemist)" title="David Baker (biochemist)">David Baker</a>'s lab, was designed completely using protein design algorithms, to a completely novel fold.<sup id="cite_ref-kuhlman03_6-2" class="reference"><a href="#cite_note-kuhlman03-6"><span class="cite-bracket">[</span>6<span class="cite-bracket">]</span></a></sup> More recently, Baker and coworkers developed a series of principles to design ideal <a href="/wiki/Globular_protein" title="Globular protein">globular-protein</a> structures based on <a href="/wiki/Folding_funnel" title="Folding funnel">protein folding funnels</a> that bridge between secondary structure prediction and tertiary structures. These principles, which build on both protein structure prediction and protein design, were used to design five different novel protein topologies.<sup id="cite_ref-9" class="reference"><a href="#cite_note-9"><span class="cite-bracket">[</span>9<span class="cite-bracket">]</span></a></sup> </p> <div class="mw-heading mw-heading3"><h3 id="Sequence_space">Sequence space</h3><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Protein_design&action=edit&section=4" title="Edit section: Sequence space"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <figure class="mw-default-size" typeof="mw:File/Thumb"><a href="/wiki/File:1FSVblue-1ZAAred.png" class="mw-file-description"><img src="//upload.wikimedia.org/wikipedia/commons/thumb/6/61/1FSVblue-1ZAAred.png/220px-1FSVblue-1ZAAred.png" decoding="async" width="220" height="205" class="mw-file-element" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/6/61/1FSVblue-1ZAAred.png/330px-1FSVblue-1ZAAred.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/6/61/1FSVblue-1ZAAred.png/440px-1FSVblue-1ZAAred.png 2x" data-file-width="567" data-file-height="528" /></a><figcaption>FSD-1 (shown in blue, PDB id: 1FSV) was the first <i>de novo</i> computational design of a full protein.<sup id="cite_ref-dahiyat1997_3-1" class="reference"><a href="#cite_note-dahiyat1997-3"><span class="cite-bracket">[</span>3<span class="cite-bracket">]</span></a></sup> The target fold was that of the zinc finger in residues 33–60 of the structure of protein Zif268 (shown in red, PDB id: 1ZAA). The designed sequence had very little sequence identity with any known protein sequence.</figcaption></figure> <p>In rational protein design, proteins can be redesigned from the sequence and structure of a known protein, or completely from scratch in <i>de novo</i> protein design. In protein redesign, most of the residues in the sequence are maintained as their wild-type amino-acid while a few are allowed to mutate. In <i>de novo</i> design, the entire sequence is designed anew, based on no prior sequence. </p><p>Both <i>de novo</i> designs and protein redesigns can establish rules on the <a href="/wiki/Sequence_space_(evolution)" title="Sequence space (evolution)">sequence space</a>: the specific amino acids that are allowed at each mutable residue position. For example, the composition of the surface of the <a href="#Protein_resurfacing">RSC3 probe</a> to select HIV-broadly neutralizing antibodies was restricted based on evolutionary data and charge balancing. Many of the earliest attempts on protein design were heavily based on empiric <i>rules</i> on the sequence space.<sup id="cite_ref-richardson1989_2-3" class="reference"><a href="#cite_note-richardson1989-2"><span class="cite-bracket">[</span>2<span class="cite-bracket">]</span></a></sup> Moreover, the <a href="#Design_of_fibrous_proteins">design of fibrous proteins</a> usually follows strict rules on the sequence space. <a href="/wiki/Collagen" title="Collagen">Collagen</a>-based designed proteins, for example, are often composed of Gly-Pro-X repeating patterns.<sup id="cite_ref-richardson1989_2-4" class="reference"><a href="#cite_note-richardson1989-2"><span class="cite-bracket">[</span>2<span class="cite-bracket">]</span></a></sup> The advent of computational techniques allows designing proteins with no human intervention in sequence selection.<sup id="cite_ref-dahiyat1997_3-2" class="reference"><a href="#cite_note-dahiyat1997-3"><span class="cite-bracket">[</span>3<span class="cite-bracket">]</span></a></sup> </p> <div class="mw-heading mw-heading3"><h3 id="Structural_flexibility">Structural flexibility</h3><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Protein_design&action=edit&section=5" title="Edit section: Structural flexibility"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <figure class="mw-halign-left" typeof="mw:File/Thumb"><a href="/wiki/File:IleRotamers.gif" class="mw-file-description"><img src="//upload.wikimedia.org/wikipedia/commons/thumb/0/08/IleRotamers.gif/200px-IleRotamers.gif" decoding="async" width="200" height="200" class="mw-file-element" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/0/08/IleRotamers.gif/300px-IleRotamers.gif 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/0/08/IleRotamers.gif/400px-IleRotamers.gif 2x" data-file-width="800" data-file-height="800" /></a><figcaption>Common protein design programs use rotamer libraries to simplify the conformational space of protein side chains. This animation loops through all the rotamers of the isoleucine amino acid based on the Penultimate Rotamer Library (total of 7 rotamers).<sup id="cite_ref-lovell2000_10-0" class="reference"><a href="#cite_note-lovell2000-10"><span class="cite-bracket">[</span>10<span class="cite-bracket">]</span></a></sup></figcaption></figure> <p>In protein design, the target structure (or structures) of the protein are known. However, a rational protein design approach must model some <i>flexibility</i> on the target structure in order to increase the number of sequences that can be designed for that structure and to minimize the chance of a sequence folding to a different structure. For example, in a protein redesign of one small amino acid (such as alanine) in the tightly packed core of a protein, very few mutants would be predicted by a rational design approach to fold to the target structure, if the surrounding side-chains are not allowed to be repacked. </p><p>Thus, an essential parameter of any design process is the amount of flexibility allowed for both the side-chains and the backbone. In the simplest models, the protein backbone is kept rigid while some of the protein side-chains are allowed to change conformations. However, side-chains can have many degrees of freedom in their bond lengths, bond angles, and <a href="/wiki/Dihedral_angle#Dihedral_angles_of_biological_molecules" title="Dihedral angle"><var>χ</var> dihedral angles</a>. To simplify this space, protein design methods use rotamer libraries that assume ideal values for bond lengths and bond angles, while restricting <var>χ</var> dihedral angles to a few frequently observed low-energy conformations termed <a href="/wiki/Conformational_isomerism" class="mw-redirect" title="Conformational isomerism">rotamers</a>. </p><p>Rotamer libraries are derived from the statistical analysis of many protein structures. Backbone-independent rotamer libraries describe all rotamers.<sup id="cite_ref-lovell2000_10-1" class="reference"><a href="#cite_note-lovell2000-10"><span class="cite-bracket">[</span>10<span class="cite-bracket">]</span></a></sup> <a href="/wiki/Backbone-dependent_rotamer_library" title="Backbone-dependent rotamer library">Backbone-dependent rotamer libraries</a>, in contrast, describe the rotamers as how likely they are to appear depending on the protein backbone arrangement around the side chain.<sup id="cite_ref-11" class="reference"><a href="#cite_note-11"><span class="cite-bracket">[</span>11<span class="cite-bracket">]</span></a></sup> Most protein design programs use one conformation (e.g., the modal value for rotamer dihedrals in space) or several points in the region described by the rotamer; the OSPREY protein design program, in contrast, models the entire continuous region.<sup id="cite_ref-samish11_12-0" class="reference"><a href="#cite_note-samish11-12"><span class="cite-bracket">[</span>12<span class="cite-bracket">]</span></a></sup> </p><p>Although rational protein design must preserve the general backbone fold a protein, allowing some backbone flexibility can significantly increase the number of sequences that fold to the structure while maintaining the general fold of the protein.<sup id="cite_ref-kortemme09_13-0" class="reference"><a href="#cite_note-kortemme09-13"><span class="cite-bracket">[</span>13<span class="cite-bracket">]</span></a></sup> Backbone flexibility is especially important in protein redesign because sequence mutations often result in small changes to the backbone structure. Moreover, backbone flexibility can be essential for more advanced applications of protein design, such as binding prediction and enzyme design. Some models of protein design backbone flexibility include small and continuous global backbone movements, discrete backbone samples around the target fold, backrub motions, and protein loop flexibility.<sup id="cite_ref-kortemme09_13-1" class="reference"><a href="#cite_note-kortemme09-13"><span class="cite-bracket">[</span>13<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-donald10_14-0" class="reference"><a href="#cite_note-donald10-14"><span class="cite-bracket">[</span>14<span class="cite-bracket">]</span></a></sup> </p> <div class="mw-heading mw-heading3"><h3 id="Energy_function">Energy function</h3><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Protein_design&action=edit&section=6" title="Edit section: Energy function"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <figure class="mw-halign-right" typeof="mw:File/Thumb"><a href="/wiki/File:PEF_comparison.png" class="mw-file-description"><img src="//upload.wikimedia.org/wikipedia/commons/thumb/4/43/PEF_comparison.png/400px-PEF_comparison.png" decoding="async" width="400" height="153" class="mw-file-element" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/4/43/PEF_comparison.png/600px-PEF_comparison.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/4/43/PEF_comparison.png/800px-PEF_comparison.png 2x" data-file-width="3976" data-file-height="1516" /></a><figcaption>Comparison of various potential energy functions. The most accurate energy are those that use quantum mechanical calculations, but these are too slow for protein design. On the other extreme, heuristic energy functions are based on statistical terms and are very fast. In the middle are molecular mechanics energy functions that are physically based but are not as computationally expensive as quantum mechanical simulations.<sup id="cite_ref-Boas_15-0" class="reference"><a href="#cite_note-Boas-15"><span class="cite-bracket">[</span>15<span class="cite-bracket">]</span></a></sup></figcaption></figure> <p>Rational protein design techniques must be able to discriminate sequences that will be stable under the target fold from those that would prefer other low-energy competing states. Thus, protein design requires accurate <a href="/wiki/Force_field_(chemistry)" title="Force field (chemistry)">energy functions</a> that can rank and score sequences by how well they fold to the target structure. At the same time, however, these energy functions must consider the computational <a href="#As_an_optimization_problem">challenges</a> behind protein design. One of the most challenging requirements for successful design is an energy function that is both accurate and simple for computational calculations. </p><p>The most accurate energy functions are those based on quantum mechanical simulations. However, such simulations are too slow and typically impractical for protein design. Instead, many protein design algorithms use either physics-based energy functions adapted from <a href="/wiki/Molecular_mechanics" title="Molecular mechanics">molecular mechanics</a> simulation programs, <a href="/wiki/Statistical_potential" title="Statistical potential">knowledge based energy-functions</a>, or a hybrid mix of both. The trend has been toward using more physics-based potential energy functions.<sup id="cite_ref-Boas_15-1" class="reference"><a href="#cite_note-Boas-15"><span class="cite-bracket">[</span>15<span class="cite-bracket">]</span></a></sup> </p><p>Physics-based energy functions, such as <a href="/wiki/AMBER" title="AMBER">AMBER</a> and <a href="/wiki/CHARMM" title="CHARMM">CHARMM</a>, are typically derived from quantum mechanical simulations, and experimental data from thermodynamics, crystallography, and spectroscopy.<sup id="cite_ref-boas2007_16-0" class="reference"><a href="#cite_note-boas2007-16"><span class="cite-bracket">[</span>16<span class="cite-bracket">]</span></a></sup> These energy functions typically simplify physical energy function and make them pairwise decomposable, meaning that the total energy of a protein conformation can be calculated by adding the pairwise energy between each atom pair, which makes them attractive for optimization algorithms. Physics-based energy functions typically model an attractive-repulsive <a href="/wiki/Lennard-Jones" class="mw-redirect" title="Lennard-Jones">Lennard-Jones</a> term between atoms and a pairwise <a href="/wiki/Electrostatics" title="Electrostatics">electrostatics</a> coulombic term<sup id="cite_ref-17" class="reference"><a href="#cite_note-17"><span class="cite-bracket">[</span>17<span class="cite-bracket">]</span></a></sup> between non-bonded atoms. </p> <figure class="mw-default-size mw-halign-left" typeof="mw:File/Thumb"><a href="/wiki/File:Water-hbond-vrc01-gp120.png" class="mw-file-description"><img src="//upload.wikimedia.org/wikipedia/commons/thumb/c/c0/Water-hbond-vrc01-gp120.png/220px-Water-hbond-vrc01-gp120.png" decoding="async" width="220" height="220" class="mw-file-element" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/c/c0/Water-hbond-vrc01-gp120.png/330px-Water-hbond-vrc01-gp120.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/c/c0/Water-hbond-vrc01-gp120.png/440px-Water-hbond-vrc01-gp120.png 2x" data-file-width="800" data-file-height="800" /></a><figcaption>Water-mediated hydrogen bonds play a key role in protein–protein binding. One such interaction is shown between residues D457, S365 in the heavy chain of the HIV-broadly-neutralizing antibody VRC01 (green) and residues N58 and Y59 in the HIV envelope protein GP120 (purple).<sup id="cite_ref-wu2010_18-0" class="reference"><a href="#cite_note-wu2010-18"><span class="cite-bracket">[</span>18<span class="cite-bracket">]</span></a></sup></figcaption></figure> <p>Statistical potentials, in contrast to physics-based potentials, have the advantage of being fast to compute, of accounting implicitly of complex effects and being less sensitive to small changes in the protein structure.<sup id="cite_ref-19" class="reference"><a href="#cite_note-19"><span class="cite-bracket">[</span>19<span class="cite-bracket">]</span></a></sup> These energy functions are <a href="/wiki/File:Knowledge_based_potential.png" title="File:Knowledge based potential.png">based on deriving energy values</a> from frequency of appearance on a structural database. </p><p>Protein design, however, has requirements that can sometimes be limited in molecular mechanics force-fields. Molecular mechanics force-fields, which have been used mostly in molecular dynamics simulations, are optimized for the simulation of single sequences, but protein design searches through many conformations of many sequences. Thus, molecular mechanics force-fields must be tailored for protein design. In practice, protein design energy functions often incorporate both statistical terms and physics-based terms. For example, the Rosetta energy function, one of the most-used energy functions, incorporates physics-based energy terms originating in the CHARMM energy function, and statistical energy terms, such as rotamer probability and knowledge-based electrostatics. Typically, energy functions are highly customized between laboratories, and specifically tailored for every design.<sup id="cite_ref-boas2007_16-1" class="reference"><a href="#cite_note-boas2007-16"><span class="cite-bracket">[</span>16<span class="cite-bracket">]</span></a></sup> </p> <div class="mw-heading mw-heading4"><h4 id="Challenges_for_effective_design_energy_functions">Challenges for effective design energy functions</h4><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Protein_design&action=edit&section=7" title="Edit section: Challenges for effective design energy functions"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>Water makes up most of the molecules surrounding proteins and is the main driver of protein structure. Thus, modeling the interaction between water and protein is vital in protein design. The number of water molecules that interact with a protein at any given time is huge and each one has a large number of degrees of freedom and interaction partners. Instead, protein design programs model most of such water molecules as a continuum, modeling both the hydrophobic effect and solvation polarization.<sup id="cite_ref-boas2007_16-2" class="reference"><a href="#cite_note-boas2007-16"><span class="cite-bracket">[</span>16<span class="cite-bracket">]</span></a></sup> </p><p>Individual water molecules can sometimes have a crucial structural role in the core of proteins, and in protein–protein or protein–ligand interactions. Failing to model such waters can result in mispredictions of the optimal sequence of a protein–protein interface. As an alternative, water molecules can be added to rotamers. <sup id="cite_ref-boas2007_16-3" class="reference"><a href="#cite_note-boas2007-16"><span class="cite-bracket">[</span>16<span class="cite-bracket">]</span></a></sup> </p><p><br /> </p> <div class="mw-heading mw-heading2"><h2 id="As_an_optimization_problem">As an optimization problem</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Protein_design&action=edit&section=8" title="Edit section: As an optimization problem"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <figure typeof="mw:File/Thumb"><a href="/wiki/File:ProteinDesignSearch.gif" class="mw-file-description"><img src="//upload.wikimedia.org/wikipedia/commons/d/d6/ProteinDesignSearch.gif" decoding="async" width="200" height="200" class="mw-file-element" data-file-width="200" data-file-height="200" /></a><figcaption>This animation illustrates the complexity of a protein design search, which typically compares all the rotamer-conformations from all possible mutations at all residues. In this example, the residues Phe36 and His 106 are allowed to mutate to, respectively, the amino acids Tyr and Asn. Phe and Tyr have 4 rotamers each in the rotamer library, while Asn and His have 7 and 8 rotamers, respectively, in the rotamer library (from the Richardson's penultimate rotamer library<sup id="cite_ref-lovell2000_10-2" class="reference"><a href="#cite_note-lovell2000-10"><span class="cite-bracket">[</span>10<span class="cite-bracket">]</span></a></sup>). The animation loops through all (4 + 4) x (7 + 8) = 120 possibilities. The structure shown is that of myoglobin, PDB id: 1mbn.</figcaption></figure> <p>The goal of protein design is to find a protein sequence that will fold to a target structure. A protein design algorithm must, thus, search all the conformations of each sequence, with respect to the target fold, and rank sequences according to the lowest-energy conformation of each one, as determined by the protein design energy function. Thus, a typical input to the protein design algorithm is the target fold, the sequence space, the structural flexibility, and the energy function, while the output is one or more sequences that are predicted to fold stably to the target structure. </p><p>The number of candidate protein sequences, however, grows exponentially with the number of protein residues; for example, there are 20<sup>100</sup> protein sequences of length 100. Furthermore, even if amino acid side-chain conformations are limited to a few rotamers (see <a href="/w/index.php?title=Structural_flexibility&action=edit&redlink=1" class="new" title="Structural flexibility (page does not exist)">Structural flexibility</a>), this results in an exponential number of conformations for each sequence. Thus, in our 100 residue protein, and assuming that each amino acid has exactly 10 rotamers, a search algorithm that searches this space will have to search over 200<sup>100</sup> protein conformations. </p><p>The most common energy functions can be decomposed into pairwise terms between rotamers and amino acid types, which casts the problem as a combinatorial one, and powerful optimization algorithms can be used to solve it. In those cases, the total energy of each conformation belonging to each sequence can be formulated as a sum of individual and pairwise terms between residue positions. If a designer is interested only in the best sequence, the protein design algorithm only requires the lowest-energy conformation of the lowest-energy sequence. In these cases, the amino acid identity of each rotamer can be ignored and all rotamers belonging to different amino acids can be treated the same. Let <var>r</var><sub><var>i</var></sub> be a rotamer at residue position <var>i</var> in the protein chain, and <var>E(<var>r</var><sub><var>i</var></sub>)</var> the potential energy between the internal atoms of the rotamer. Let <var>E</var>(<var>r</var><sub><var>i</var></sub>, <var>r</var><sub><var>j</var></sub>) be the potential energy between <var>r</var><sub><var>i</var></sub> and rotamer <var>r</var><sub><var>j</var></sub> at residue position <var>j</var>. Then, we define the optimization problem as one of finding the conformation of minimum energy (<var>E</var><sub><var>T</var></sub>): </p> <style data-mw-deduplicate="TemplateStyles:r1266403038">.mw-parser-output table.numblk{border-collapse:collapse;border:none;margin-top:0;margin-right:0;margin-bottom:0}.mw-parser-output table.numblk>tbody>tr>td{vertical-align:middle;padding:0}.mw-parser-output table.numblk>tbody>tr>td:nth-child(2){width:99%}.mw-parser-output table.numblk>tbody>tr>td:nth-child(2)>table{border-collapse:collapse;margin:0;border:none;width:100%}.mw-parser-output table.numblk>tbody>tr>td:nth-child(2)>table>tbody>tr:first-child>td:first-child,.mw-parser-output table.numblk>tbody>tr>td:nth-child(2)>table>tbody>tr:first-child>td:last-child{padding:0 0.4ex}.mw-parser-output table.numblk>tbody>tr>td:nth-child(2)>table>tbody>tr:first-child>td:nth-child(2){width:100%;padding:0}.mw-parser-output table.numblk>tbody>tr>td:nth-child(2)>table>tbody>tr:last-child>td{padding:0}.mw-parser-output table.numblk>tbody>tr>td:last-child{font-weight:bold}.mw-parser-output table.numblk.numblk-raw-n>tbody>tr>td:last-child{font-weight:unset}.mw-parser-output table.numblk>tbody>tr>td:last-child::before{content:"("}.mw-parser-output table.numblk>tbody>tr>td:last-child::after{content:")"}.mw-parser-output table.numblk.numblk-raw-n>tbody>tr>td:last-child::before,.mw-parser-output table.numblk.numblk-raw-n>tbody>tr>td:last-child::after{content:none}.mw-parser-output table.numblk>tbody>tr>td{border:none}.mw-parser-output table.numblk.numblk-border>tbody>tr>td{border:thin solid}.mw-parser-output table.numblk>tbody>tr>td:nth-child(2)>table>tbody>tr:first-child>td{border:none}.mw-parser-output table.numblk.numblk-border>tbody>tr>td:nth-child(2)>table>tbody>tr:first-child>td{border:thin solid}.mw-parser-output table.numblk>tbody>tr>td:nth-child(2)>table>tbody>tr:last-child>td{border-left:none;border-right:none;border-bottom:none}.mw-parser-output table.numblk.numblk-border>tbody>tr>td:nth-child(2)>table>tbody>tr:last-child>td{border-left:thin solid;border-right:thin solid;border-bottom:thin solid}.mw-parser-output table.numblk:target{color:var(--color-base,#202122);background-color:#cfe8fd}@media screen{html.skin-theme-clientpref-night .mw-parser-output table.numblk:target{color:var(--color-base,#eaecf0);background-color:#301702}}@media screen and (prefers-color-scheme:dark){html.skin-theme-clientpref-os .mw-parser-output table.numblk:target{color:var(--color-base,#eaecf0);background-color:#301702}}</style><table role="presentation" class="numblk" style="margin-left: 1.6em;"><tbody><tr><td class="nowrap"><span class="mwe-math-element"><span class="mwe-math-mathml-inline mwe-math-mathml-a11y" style="display: none;"><math xmlns="http://www.w3.org/1998/Math/MathML" alttext="{\displaystyle \min E_{T}=\sum _{i}{\Big [}E_{i}(r_{i})+\sum _{i\neq j}E_{ij}(r_{i},r_{j}){\Big ]}\,}"> <semantics> <mrow class="MJX-TeXAtom-ORD"> <mstyle displaystyle="true" scriptlevel="0"> <mo movablelimits="true" form="prefix">min</mo> <msub> <mi>E</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>T</mi> </mrow> </msub> <mo>=</mo> <munder> <mo>∑</mo> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> </mrow> </munder> <mrow class="MJX-TeXAtom-ORD"> <mrow class="MJX-TeXAtom-ORD"> <mo maxsize="1.623em" minsize="1.623em">[</mo> </mrow> </mrow> <msub> <mi>E</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> </mrow> </msub> <mo stretchy="false">(</mo> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> </mrow> </msub> <mo stretchy="false">)</mo> <mo>+</mo> <munder> <mo>∑</mo> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> <mo>≠</mo> <mi>j</mi> </mrow> </munder> <msub> <mi>E</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> <mi>j</mi> </mrow> </msub> <mo stretchy="false">(</mo> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> </mrow> </msub> <mo>,</mo> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>j</mi> </mrow> </msub> <mo stretchy="false">)</mo> <mrow class="MJX-TeXAtom-ORD"> <mrow class="MJX-TeXAtom-ORD"> <mo maxsize="1.623em" minsize="1.623em">]</mo> </mrow> </mrow> <mspace width="thinmathspace" /> </mstyle> </mrow> <annotation encoding="application/x-tex">{\displaystyle \min E_{T}=\sum _{i}{\Big [}E_{i}(r_{i})+\sum _{i\neq j}E_{ij}(r_{i},r_{j}){\Big ]}\,}</annotation> </semantics> </math></span><img src="https://wikimedia.org/api/rest_v1/media/math/render/svg/3332d826843218136390cef20e4ee8e3694fc477" class="mwe-math-fallback-image-inline mw-invert skin-invert" aria-hidden="true" style="vertical-align: -3.505ex; width:39.387ex; height:6.509ex;" alt="{\displaystyle \min E_{T}=\sum _{i}{\Big [}E_{i}(r_{i})+\sum _{i\neq j}E_{ij}(r_{i},r_{j}){\Big ]}\,}"></span></td> <td></td> <td class="nowrap"><span id="math_1" class="reference nourlexpansion" style="font-weight:bold;">1</span></td></tr></tbody></table> <p>The problem of minimizing <var>E<sub>T</sub></var> is an <a href="/wiki/NP-hard" class="mw-redirect" title="NP-hard">NP-hard</a> problem.<sup id="cite_ref-donald10_14-1" class="reference"><a href="#cite_note-donald10-14"><span class="cite-bracket">[</span>14<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-20" class="reference"><a href="#cite_note-20"><span class="cite-bracket">[</span>20<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-voigt00_21-0" class="reference"><a href="#cite_note-voigt00-21"><span class="cite-bracket">[</span>21<span class="cite-bracket">]</span></a></sup> Even though the class of problems is NP-hard, in practice many instances of protein design can be solved exactly or optimized satisfactorily through heuristic methods. </p> <div class="mw-heading mw-heading2"><h2 id="Algorithms">Algorithms</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Protein_design&action=edit&section=9" title="Edit section: Algorithms"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>Several algorithms have been developed specifically for the protein design problem. These algorithms can be divided into two broad classes: exact algorithms, such as <a href="/wiki/Dead-end_elimination" title="Dead-end elimination">dead-end elimination</a>, that lack <a href="/wiki/Run_time_(program_lifecycle_phase)" class="mw-redirect" title="Run time (program lifecycle phase)">runtime</a> guarantees but guarantee the quality of the solution; and <a href="/wiki/Heuristic_(computer_science)" title="Heuristic (computer science)">heuristic</a> algorithms, such as Monte Carlo, that are faster than exact algorithms but have no guarantees on the optimality of the results. Exact algorithms guarantee that the optimization process produced the optimal according to the protein design model. Thus, if the predictions of exact algorithms fail when these are experimentally validated, then the source of error can be attributed to the energy function, the allowed flexibility, the sequence space or the target structure (e.g., if it cannot be designed for).<sup id="cite_ref-22" class="reference"><a href="#cite_note-22"><span class="cite-bracket">[</span>22<span class="cite-bracket">]</span></a></sup> </p><p>Some protein design algorithms are listed below. Although these algorithms address only the most basic formulation of the protein design problem, Equation (<b><a href="#math_1">1</a></b>), when the optimization goal changes because designers introduce improvements and extensions to the protein design model, such as improvements to the structural flexibility allowed (e.g., protein backbone flexibility) or including sophisticated energy terms, many of the extensions on protein design that improve modeling are built atop these algorithms. For example, Rosetta Design incorporates sophisticated energy terms, and backbone flexibility using Monte Carlo as the underlying optimizing algorithm. OSPREY's algorithms build on the dead-end elimination algorithm and A* to incorporate continuous backbone and side-chain movements. Thus, these algorithms provide a good perspective on the different kinds of algorithms available for protein design. </p><p>In 2020 scientists reported the development of an AI-based process using <a href="/wiki/List_of_biological_databases" title="List of biological databases">genome databases</a> for <a href="/wiki/Evolutionary_algorithm" title="Evolutionary algorithm">evolution-based</a> designing of novel proteins. They used <a href="/wiki/Deep_learning" title="Deep learning">deep learning</a> to identify design-rules.<sup id="cite_ref-23" class="reference"><a href="#cite_note-23"><span class="cite-bracket">[</span>23<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-24" class="reference"><a href="#cite_note-24"><span class="cite-bracket">[</span>24<span class="cite-bracket">]</span></a></sup> In 2022, a study reported deep learning software that can design proteins that contain prespecified functional sites.<sup id="cite_ref-25" class="reference"><a href="#cite_note-25"><span class="cite-bracket">[</span>25<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-26" class="reference"><a href="#cite_note-26"><span class="cite-bracket">[</span>26<span class="cite-bracket">]</span></a></sup> </p> <div class="mw-heading mw-heading3"><h3 id="With_mathematical_guarantees">With mathematical guarantees</h3><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Protein_design&action=edit&section=10" title="Edit section: With mathematical guarantees"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <div class="mw-heading mw-heading4"><h4 id="Dead-end_elimination">Dead-end elimination</h4><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Protein_design&action=edit&section=11" title="Edit section: Dead-end elimination"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1236090951"><div role="note" class="hatnote navigation-not-searchable">Main article: <a href="/wiki/Dead-end_elimination" title="Dead-end elimination">Dead-end elimination</a></div> <p>The dead-end elimination (DEE) algorithm reduces the search space of the problem iteratively by removing rotamers that can be provably shown to be not part of the global lowest energy conformation (GMEC). On each iteration, the dead-end elimination algorithm compares all possible pairs of rotamers at each residue position, and removes each rotamer <var>r′<sub>i</sub></var> that can be shown to always be of higher energy than another rotamer <var>r<sub>i</sub></var> and is thus not part of the GMEC: </p> <dl><dd><span class="mwe-math-element"><span class="mwe-math-mathml-inline mwe-math-mathml-a11y" style="display: none;"><math xmlns="http://www.w3.org/1998/Math/MathML" alttext="{\displaystyle E(r_{i}^{\prime })+\sum _{j\neq i}\min _{r_{j}}E(r_{i}^{\prime },r_{j})>E(r_{i})+\sum _{j\neq i}\max _{r_{j}}E(r_{i},r_{j})}"> <semantics> <mrow class="MJX-TeXAtom-ORD"> <mstyle displaystyle="true" scriptlevel="0"> <mi>E</mi> <mo stretchy="false">(</mo> <msubsup> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> </mrow> <mrow class="MJX-TeXAtom-ORD"> <mi class="MJX-variant" mathvariant="normal">′</mi> </mrow> </msubsup> <mo stretchy="false">)</mo> <mo>+</mo> <munder> <mo>∑</mo> <mrow class="MJX-TeXAtom-ORD"> <mi>j</mi> <mo>≠</mo> <mi>i</mi> </mrow> </munder> <munder> <mo movablelimits="true" form="prefix">min</mo> <mrow class="MJX-TeXAtom-ORD"> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>j</mi> </mrow> </msub> </mrow> </munder> <mi>E</mi> <mo stretchy="false">(</mo> <msubsup> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> </mrow> <mrow class="MJX-TeXAtom-ORD"> <mi class="MJX-variant" mathvariant="normal">′</mi> </mrow> </msubsup> <mo>,</mo> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>j</mi> </mrow> </msub> <mo stretchy="false">)</mo> <mo>></mo> <mi>E</mi> <mo stretchy="false">(</mo> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> </mrow> </msub> <mo stretchy="false">)</mo> <mo>+</mo> <munder> <mo>∑</mo> <mrow class="MJX-TeXAtom-ORD"> <mi>j</mi> <mo>≠</mo> <mi>i</mi> </mrow> </munder> <munder> <mo movablelimits="true" form="prefix">max</mo> <mrow class="MJX-TeXAtom-ORD"> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>j</mi> </mrow> </msub> </mrow> </munder> <mi>E</mi> <mo stretchy="false">(</mo> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> </mrow> </msub> <mo>,</mo> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>j</mi> </mrow> </msub> <mo stretchy="false">)</mo> </mstyle> </mrow> <annotation encoding="application/x-tex">{\displaystyle E(r_{i}^{\prime })+\sum _{j\neq i}\min _{r_{j}}E(r_{i}^{\prime },r_{j})>E(r_{i})+\sum _{j\neq i}\max _{r_{j}}E(r_{i},r_{j})}</annotation> </semantics> </math></span><img src="https://wikimedia.org/api/rest_v1/media/math/render/svg/c21bfdfd3daf44b542d41774c61cd482f905bb34" class="mwe-math-fallback-image-inline mw-invert skin-invert" aria-hidden="true" style="vertical-align: -3.505ex; width:52.956ex; height:6.009ex;" alt="{\displaystyle E(r_{i}^{\prime })+\sum _{j\neq i}\min _{r_{j}}E(r_{i}^{\prime },r_{j})>E(r_{i})+\sum _{j\neq i}\max _{r_{j}}E(r_{i},r_{j})}"></span></dd></dl> <p>Other powerful extensions to the dead-end elimination algorithm include the <a href="/wiki/Dead-end_elimination#Pairs_elimination_criterion" title="Dead-end elimination">pairs elimination criterion</a>, and the <a href="/wiki/Dead-end_elimination#Generalization" title="Dead-end elimination">generalized dead-end elimination criterion</a>. This algorithm has also been extended to handle continuous rotamers with provable guarantees. </p><p>Although the Dead-end elimination algorithm runs in polynomial time on each iteration, it cannot guarantee convergence. If, after a certain number of iterations, the dead-end elimination algorithm does not prune any more rotamers, then either rotamers have to be merged or another search algorithm must be used to search the remaining search space. In such cases, the dead-end elimination acts as a pre-filtering algorithm to reduce the search space, while other algorithms, such as A*, Monte Carlo, Linear Programming, or FASTER are used to search the remaining search space.<sup id="cite_ref-donald10_14-2" class="reference"><a href="#cite_note-donald10-14"><span class="cite-bracket">[</span>14<span class="cite-bracket">]</span></a></sup> </p> <div class="mw-heading mw-heading4"><h4 id="Branch_and_bound">Branch and bound</h4><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Protein_design&action=edit&section=12" title="Edit section: Branch and bound"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1236090951"><div role="note" class="hatnote navigation-not-searchable">Main article: <a href="/wiki/Branch_and_bound" title="Branch and bound">Branch and bound</a></div> <p>The protein design conformational space can be represented as a <a href="/wiki/Tree_(data_structure)" class="mw-redirect" title="Tree (data structure)">tree</a>, where the protein residues are ordered in an arbitrary way, and the tree branches at each of the rotamers in a residue. <a href="/wiki/Branch_and_bound" title="Branch and bound">Branch and bound</a> algorithms use this representation to efficiently explore the conformation tree: At each <i>branching</i>, branch and bound algorithms <i>bound</i> the conformation space and explore only the promising branches.<sup id="cite_ref-donald10_14-3" class="reference"><a href="#cite_note-donald10-14"><span class="cite-bracket">[</span>14<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-gordon99_27-0" class="reference"><a href="#cite_note-gordon99-27"><span class="cite-bracket">[</span>27<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-leach98_28-0" class="reference"><a href="#cite_note-leach98-28"><span class="cite-bracket">[</span>28<span class="cite-bracket">]</span></a></sup> </p><p>A popular search algorithm for protein design is the <a href="/wiki/A*_search_algorithm" title="A* search algorithm">A* search algorithm</a>.<sup id="cite_ref-donald10_14-4" class="reference"><a href="#cite_note-donald10-14"><span class="cite-bracket">[</span>14<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-leach98_28-1" class="reference"><a href="#cite_note-leach98-28"><span class="cite-bracket">[</span>28<span class="cite-bracket">]</span></a></sup> A* computes a lower-bound score on each partial tree path that lower bounds (with guarantees) the energy of each of the expanded rotamers. Each partial conformation is added to a priority queue and at each iteration the partial path with the lowest lower bound is popped from the queue and expanded. The algorithm stops once a full conformation has been enumerated and guarantees that the conformation is the optimal. </p><p>The A* score <var>f</var> in protein design consists of two parts, <var>f=g+h</var>. <var>g</var> is the exact energy of the rotamers that have already been assigned in the partial conformation. <var>h</var> is a lower bound on the energy of the rotamers that have not yet been assigned. Each is designed as follows, where <var>d</var> is the index of the last assigned residue in the partial conformation. </p> <dl><dd><span class="mwe-math-element"><span class="mwe-math-mathml-inline mwe-math-mathml-a11y" style="display: none;"><math xmlns="http://www.w3.org/1998/Math/MathML" alttext="{\displaystyle g=\sum _{i=1}^{d}(E(r_{i})+\sum _{j=i+1}^{d}E(r_{i},r_{j}))}"> <semantics> <mrow class="MJX-TeXAtom-ORD"> <mstyle displaystyle="true" scriptlevel="0"> <mi>g</mi> <mo>=</mo> <munderover> <mo>∑</mo> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> <mo>=</mo> <mn>1</mn> </mrow> <mrow class="MJX-TeXAtom-ORD"> <mi>d</mi> </mrow> </munderover> <mo stretchy="false">(</mo> <mi>E</mi> <mo stretchy="false">(</mo> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> </mrow> </msub> <mo stretchy="false">)</mo> <mo>+</mo> <munderover> <mo>∑</mo> <mrow class="MJX-TeXAtom-ORD"> <mi>j</mi> <mo>=</mo> <mi>i</mi> <mo>+</mo> <mn>1</mn> </mrow> <mrow class="MJX-TeXAtom-ORD"> <mi>d</mi> </mrow> </munderover> <mi>E</mi> <mo stretchy="false">(</mo> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> </mrow> </msub> <mo>,</mo> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>j</mi> </mrow> </msub> <mo stretchy="false">)</mo> <mo stretchy="false">)</mo> </mstyle> </mrow> <annotation encoding="application/x-tex">{\displaystyle g=\sum _{i=1}^{d}(E(r_{i})+\sum _{j=i+1}^{d}E(r_{i},r_{j}))}</annotation> </semantics> </math></span><img src="https://wikimedia.org/api/rest_v1/media/math/render/svg/9c1b7d1ba3ea0355da7b8cd7c1387b88b3724e88" class="mwe-math-fallback-image-inline mw-invert skin-invert" aria-hidden="true" style="vertical-align: -3.338ex; width:31.089ex; height:7.676ex;" alt="{\displaystyle g=\sum _{i=1}^{d}(E(r_{i})+\sum _{j=i+1}^{d}E(r_{i},r_{j}))}"></span></dd></dl> <dl><dd><span class="mwe-math-element"><span class="mwe-math-mathml-inline mwe-math-mathml-a11y" style="display: none;"><math xmlns="http://www.w3.org/1998/Math/MathML" alttext="{\displaystyle h=\sum _{j=d+1}^{n}[\min _{r_{j}}(E(r_{j})+\sum _{i=1}^{d}E(r_{i},r_{j})+\sum _{k=j+1}^{n}\min _{r_{k}}E(r_{j},r_{k}))]}"> <semantics> <mrow class="MJX-TeXAtom-ORD"> <mstyle displaystyle="true" scriptlevel="0"> <mi>h</mi> <mo>=</mo> <munderover> <mo>∑</mo> <mrow class="MJX-TeXAtom-ORD"> <mi>j</mi> <mo>=</mo> <mi>d</mi> <mo>+</mo> <mn>1</mn> </mrow> <mrow class="MJX-TeXAtom-ORD"> <mi>n</mi> </mrow> </munderover> <mo stretchy="false">[</mo> <munder> <mo movablelimits="true" form="prefix">min</mo> <mrow class="MJX-TeXAtom-ORD"> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>j</mi> </mrow> </msub> </mrow> </munder> <mo stretchy="false">(</mo> <mi>E</mi> <mo stretchy="false">(</mo> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>j</mi> </mrow> </msub> <mo stretchy="false">)</mo> <mo>+</mo> <munderover> <mo>∑</mo> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> <mo>=</mo> <mn>1</mn> </mrow> <mrow class="MJX-TeXAtom-ORD"> <mi>d</mi> </mrow> </munderover> <mi>E</mi> <mo stretchy="false">(</mo> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> </mrow> </msub> <mo>,</mo> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>j</mi> </mrow> </msub> <mo stretchy="false">)</mo> <mo>+</mo> <munderover> <mo>∑</mo> <mrow class="MJX-TeXAtom-ORD"> <mi>k</mi> <mo>=</mo> <mi>j</mi> <mo>+</mo> <mn>1</mn> </mrow> <mrow class="MJX-TeXAtom-ORD"> <mi>n</mi> </mrow> </munderover> <munder> <mo movablelimits="true" form="prefix">min</mo> <mrow class="MJX-TeXAtom-ORD"> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>k</mi> </mrow> </msub> </mrow> </munder> <mi>E</mi> <mo stretchy="false">(</mo> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>j</mi> </mrow> </msub> <mo>,</mo> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>k</mi> </mrow> </msub> <mo stretchy="false">)</mo> <mo stretchy="false">)</mo> <mo stretchy="false">]</mo> </mstyle> </mrow> <annotation encoding="application/x-tex">{\displaystyle h=\sum _{j=d+1}^{n}[\min _{r_{j}}(E(r_{j})+\sum _{i=1}^{d}E(r_{i},r_{j})+\sum _{k=j+1}^{n}\min _{r_{k}}E(r_{j},r_{k}))]}</annotation> </semantics> </math></span><img src="https://wikimedia.org/api/rest_v1/media/math/render/svg/e143d714d94f81766d65c1ab49da42eeeed08b4a" class="mwe-math-fallback-image-inline mw-invert skin-invert" aria-hidden="true" style="vertical-align: -3.338ex; width:58.001ex; height:7.676ex;" alt="{\displaystyle h=\sum _{j=d+1}^{n}[\min _{r_{j}}(E(r_{j})+\sum _{i=1}^{d}E(r_{i},r_{j})+\sum _{k=j+1}^{n}\min _{r_{k}}E(r_{j},r_{k}))]}"></span></dd></dl> <div class="mw-heading mw-heading4"><h4 id="Integer_linear_programming">Integer linear programming</h4><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Protein_design&action=edit&section=13" title="Edit section: Integer linear programming"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1236090951"><div role="note" class="hatnote navigation-not-searchable">Further information: <a href="/wiki/Linear_programming#Integer_unknowns" title="Linear programming">Linear programming § Integer unknowns</a>, and <a href="/wiki/Integer_programming" title="Integer programming">Integer programming</a></div> <p>The problem of optimizing <var>E<sub>T</sub></var> (Equation (<b><a href="#math_1">1</a></b>)) can be easily formulated as an <a href="/wiki/Integer_linear_program" class="mw-redirect" title="Integer linear program">integer linear program</a> (ILP).<sup id="cite_ref-kingsford05_29-0" class="reference"><a href="#cite_note-kingsford05-29"><span class="cite-bracket">[</span>29<span class="cite-bracket">]</span></a></sup> One of the most powerful formulations uses binary variables to represent the presence of a rotamer and edges in the final solution, and constraints the solution to have exactly one rotamer for each residue and one pairwise interaction for each pair of residues: </p> <dl><dd><span class="mwe-math-element"><span class="mwe-math-mathml-inline mwe-math-mathml-a11y" style="display: none;"><math xmlns="http://www.w3.org/1998/Math/MathML" alttext="{\displaystyle \ \min \sum _{i}\sum _{r_{i}}E_{i}(r_{i})q_{i}(r_{i})+\sum _{j\neq i}\sum _{r_{j}}E_{ij}(r_{i},r_{j})q_{ij}(r_{i},r_{j})\,}"> <semantics> <mrow class="MJX-TeXAtom-ORD"> <mstyle displaystyle="true" scriptlevel="0"> <mtext> </mtext> <mo movablelimits="true" form="prefix">min</mo> <munder> <mo>∑</mo> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> </mrow> </munder> <munder> <mo>∑</mo> <mrow class="MJX-TeXAtom-ORD"> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> </mrow> </msub> </mrow> </munder> <msub> <mi>E</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> </mrow> </msub> <mo stretchy="false">(</mo> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> </mrow> </msub> <mo stretchy="false">)</mo> <msub> <mi>q</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> </mrow> </msub> <mo stretchy="false">(</mo> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> </mrow> </msub> <mo stretchy="false">)</mo> <mo>+</mo> <munder> <mo>∑</mo> <mrow class="MJX-TeXAtom-ORD"> <mi>j</mi> <mo>≠</mo> <mi>i</mi> </mrow> </munder> <munder> <mo>∑</mo> <mrow class="MJX-TeXAtom-ORD"> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>j</mi> </mrow> </msub> </mrow> </munder> <msub> <mi>E</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> <mi>j</mi> </mrow> </msub> <mo stretchy="false">(</mo> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> </mrow> </msub> <mo>,</mo> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>j</mi> </mrow> </msub> <mo stretchy="false">)</mo> <msub> <mi>q</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> <mi>j</mi> </mrow> </msub> <mo stretchy="false">(</mo> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> </mrow> </msub> <mo>,</mo> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>j</mi> </mrow> </msub> <mo stretchy="false">)</mo> <mspace width="thinmathspace" /> </mstyle> </mrow> <annotation encoding="application/x-tex">{\displaystyle \ \min \sum _{i}\sum _{r_{i}}E_{i}(r_{i})q_{i}(r_{i})+\sum _{j\neq i}\sum _{r_{j}}E_{ij}(r_{i},r_{j})q_{ij}(r_{i},r_{j})\,}</annotation> </semantics> </math></span><img src="https://wikimedia.org/api/rest_v1/media/math/render/svg/b8b69556d135c3f331300b793f288ace9281d6aa" class="mwe-math-fallback-image-inline mw-invert skin-invert" aria-hidden="true" style="vertical-align: -3.505ex; width:54.099ex; height:6.009ex;" alt="{\displaystyle \ \min \sum _{i}\sum _{r_{i}}E_{i}(r_{i})q_{i}(r_{i})+\sum _{j\neq i}\sum _{r_{j}}E_{ij}(r_{i},r_{j})q_{ij}(r_{i},r_{j})\,}"></span></dd></dl> <p>s.t. </p> <dl><dd><span class="mwe-math-element"><span class="mwe-math-mathml-inline mwe-math-mathml-a11y" style="display: none;"><math xmlns="http://www.w3.org/1998/Math/MathML" alttext="{\displaystyle \sum _{r_{i}}q_{i}(r_{i})=1,\ \forall i}"> <semantics> <mrow class="MJX-TeXAtom-ORD"> <mstyle displaystyle="true" scriptlevel="0"> <munder> <mo>∑</mo> <mrow class="MJX-TeXAtom-ORD"> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> </mrow> </msub> </mrow> </munder> <msub> <mi>q</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> </mrow> </msub> <mo stretchy="false">(</mo> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> </mrow> </msub> <mo stretchy="false">)</mo> <mo>=</mo> <mn>1</mn> <mo>,</mo> <mtext> </mtext> <mi mathvariant="normal">∀</mi> <mi>i</mi> </mstyle> </mrow> <annotation encoding="application/x-tex">{\displaystyle \sum _{r_{i}}q_{i}(r_{i})=1,\ \forall i}</annotation> </semantics> </math></span><img src="https://wikimedia.org/api/rest_v1/media/math/render/svg/604b5677c8072fc7975d94ba5b7727786f77a855" class="mwe-math-fallback-image-inline mw-invert skin-invert" aria-hidden="true" style="vertical-align: -3.338ex; width:17.207ex; height:5.843ex;" alt="{\displaystyle \sum _{r_{i}}q_{i}(r_{i})=1,\ \forall i}"></span></dd></dl> <dl><dd><span class="mwe-math-element"><span class="mwe-math-mathml-inline mwe-math-mathml-a11y" style="display: none;"><math xmlns="http://www.w3.org/1998/Math/MathML" alttext="{\displaystyle \sum _{r_{j}}q_{ij}(r_{i},r_{j})=q_{i}(r_{i}),\forall i,r_{i},j}"> <semantics> <mrow class="MJX-TeXAtom-ORD"> <mstyle displaystyle="true" scriptlevel="0"> <munder> <mo>∑</mo> <mrow class="MJX-TeXAtom-ORD"> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>j</mi> </mrow> </msub> </mrow> </munder> <msub> <mi>q</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> <mi>j</mi> </mrow> </msub> <mo stretchy="false">(</mo> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> </mrow> </msub> <mo>,</mo> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>j</mi> </mrow> </msub> <mo stretchy="false">)</mo> <mo>=</mo> <msub> <mi>q</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> </mrow> </msub> <mo stretchy="false">(</mo> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> </mrow> </msub> <mo stretchy="false">)</mo> <mo>,</mo> <mi mathvariant="normal">∀</mi> <mi>i</mi> <mo>,</mo> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> </mrow> </msub> <mo>,</mo> <mi>j</mi> </mstyle> </mrow> <annotation encoding="application/x-tex">{\displaystyle \sum _{r_{j}}q_{ij}(r_{i},r_{j})=q_{i}(r_{i}),\forall i,r_{i},j}</annotation> </semantics> </math></span><img src="https://wikimedia.org/api/rest_v1/media/math/render/svg/9142305f19b5f6fb9af9211cdf6322d316581eca" class="mwe-math-fallback-image-inline mw-invert skin-invert" aria-hidden="true" style="vertical-align: -3.505ex; width:29.502ex; height:6.009ex;" alt="{\displaystyle \sum _{r_{j}}q_{ij}(r_{i},r_{j})=q_{i}(r_{i}),\forall i,r_{i},j}"></span></dd></dl> <dl><dd><span class="mwe-math-element"><span class="mwe-math-mathml-inline mwe-math-mathml-a11y" style="display: none;"><math xmlns="http://www.w3.org/1998/Math/MathML" alttext="{\displaystyle q_{i},q_{ij}\in \{0,1\}}"> <semantics> <mrow class="MJX-TeXAtom-ORD"> <mstyle displaystyle="true" scriptlevel="0"> <msub> <mi>q</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> </mrow> </msub> <mo>,</mo> <msub> <mi>q</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> <mi>j</mi> </mrow> </msub> <mo>∈</mo> <mo fence="false" stretchy="false">{</mo> <mn>0</mn> <mo>,</mo> <mn>1</mn> <mo fence="false" stretchy="false">}</mo> </mstyle> </mrow> <annotation encoding="application/x-tex">{\displaystyle q_{i},q_{ij}\in \{0,1\}}</annotation> </semantics> </math></span><img src="https://wikimedia.org/api/rest_v1/media/math/render/svg/cb0d7bf68da27b3cba788db349d71eabd2a77bd0" class="mwe-math-fallback-image-inline mw-invert skin-invert" aria-hidden="true" style="vertical-align: -1.005ex; width:13.909ex; height:3.009ex;" alt="{\displaystyle q_{i},q_{ij}\in \{0,1\}}"></span></dd></dl> <p>ILP solvers, such as <a href="/wiki/CPLEX" title="CPLEX">CPLEX</a>, can compute the exact optimal solution for large instances of protein design problems. These solvers use a <a href="/wiki/Linear_programming_relaxation" title="Linear programming relaxation">linear programming relaxation</a> of the problem, where <var>q<sub>i</sub></var> and <var>q<sub>ij</sub></var> are allowed to take continuous values, in combination with a <a href="/wiki/Branch_and_cut" title="Branch and cut">branch and cut</a> algorithm to search only a small portion of the conformation space for the optimal solution. ILP solvers have been shown to solve many instances of the side-chain placement problem.<sup id="cite_ref-kingsford05_29-1" class="reference"><a href="#cite_note-kingsford05-29"><span class="cite-bracket">[</span>29<span class="cite-bracket">]</span></a></sup> </p> <div class="mw-heading mw-heading4"><h4 id="Message-passing_based_approximations_to_the_linear_programming_dual">Message-passing based approximations to the linear programming dual</h4><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Protein_design&action=edit&section=14" title="Edit section: Message-passing based approximations to the linear programming dual"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>ILP solvers depend on linear programming (LP) algorithms, such as the <a href="/wiki/Simplex_algorithm" title="Simplex algorithm">Simplex</a> or <a href="/wiki/Barrier_function" title="Barrier function">barrier</a>-based methods to perform the LP relaxation at each branch. These LP algorithms were developed as general-purpose optimization methods and are not optimized for the protein design problem (Equation (<b><a href="#math_1">1</a></b>)). In consequence, the LP relaxation becomes the bottleneck of ILP solvers when the problem size is large.<sup id="cite_ref-yanover06_30-0" class="reference"><a href="#cite_note-yanover06-30"><span class="cite-bracket">[</span>30<span class="cite-bracket">]</span></a></sup> Recently, several alternatives based on <a href="/wiki/Belief_propagation" title="Belief propagation">message-passing algorithms</a> have been designed specifically for the optimization of the LP relaxation of the protein design problem. These algorithms can approximate both the <a href="/wiki/Duality_(optimization)" title="Duality (optimization)">dual</a> or the <a href="/wiki/Duality_(optimization)" title="Duality (optimization)">primal</a> instances of the integer programming, but in order to maintain guarantees on optimality, they are most useful when used to approximate the dual of the protein design problem, because approximating the dual guarantees that no solutions are missed. Message-passing based approximations include the <i>tree reweighted max-product message passing</i> algorithm,<sup id="cite_ref-31" class="reference"><a href="#cite_note-31"><span class="cite-bracket">[</span>31<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-32" class="reference"><a href="#cite_note-32"><span class="cite-bracket">[</span>32<span class="cite-bracket">]</span></a></sup> and the <i>message passing linear programming</i> algorithm.<sup id="cite_ref-33" class="reference"><a href="#cite_note-33"><span class="cite-bracket">[</span>33<span class="cite-bracket">]</span></a></sup> </p> <div class="mw-heading mw-heading3"><h3 id="Optimization_algorithms_without_guarantees">Optimization algorithms without guarantees</h3><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Protein_design&action=edit&section=15" title="Edit section: Optimization algorithms without guarantees"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <div class="mw-heading mw-heading4"><h4 id="Monte_Carlo_and_simulated_annealing">Monte Carlo and simulated annealing</h4><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Protein_design&action=edit&section=16" title="Edit section: Monte Carlo and simulated annealing"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>Monte Carlo is one of the most widely used algorithms for protein design. In its simplest form, a Monte Carlo algorithm selects a residue at random, and in that residue a randomly chosen rotamer (of any amino acid) is evaluated.<sup id="cite_ref-voigt00_21-1" class="reference"><a href="#cite_note-voigt00-21"><span class="cite-bracket">[</span>21<span class="cite-bracket">]</span></a></sup> The new energy of the protein, <var>E</var><sub>new</sub> is compared against the old energy <var>E</var><sub>old</sub> and the new rotamer is <i>accepted</i> with a probability of: </p> <dl><dd><span class="mwe-math-element"><span class="mwe-math-mathml-inline mwe-math-mathml-a11y" style="display: none;"><math xmlns="http://www.w3.org/1998/Math/MathML" alttext="{\displaystyle p=e^{-\beta (E_{\text{new}}-E_{\text{old}}))},}"> <semantics> <mrow class="MJX-TeXAtom-ORD"> <mstyle displaystyle="true" scriptlevel="0"> <mi>p</mi> <mo>=</mo> <msup> <mi>e</mi> <mrow class="MJX-TeXAtom-ORD"> <mo>−</mo> <mi>β</mi> <mo stretchy="false">(</mo> <msub> <mi>E</mi> <mrow class="MJX-TeXAtom-ORD"> <mtext>new</mtext> </mrow> </msub> <mo>−</mo> <msub> <mi>E</mi> <mrow class="MJX-TeXAtom-ORD"> <mtext>old</mtext> </mrow> </msub> <mo stretchy="false">)</mo> <mo stretchy="false">)</mo> </mrow> </msup> <mo>,</mo> </mstyle> </mrow> <annotation encoding="application/x-tex">{\displaystyle p=e^{-\beta (E_{\text{new}}-E_{\text{old}}))},}</annotation> </semantics> </math></span><img src="https://wikimedia.org/api/rest_v1/media/math/render/svg/d6ed9470efadc840d30d7fb2d1c075002a309727" class="mwe-math-fallback-image-inline mw-invert skin-invert" aria-hidden="true" style="vertical-align: -0.671ex; margin-left: -0.089ex; width:18.571ex; height:3.176ex;" alt="{\displaystyle p=e^{-\beta (E_{\text{new}}-E_{\text{old}}))},}"></span></dd></dl> <p>where <var>β</var> is the <a href="/wiki/Boltzmann_constant" title="Boltzmann constant">Boltzmann constant</a> and the temperature <var>T</var> can be chosen such that in the initial rounds it is high and it is slowly <a href="/wiki/Simulated_annealing" title="Simulated annealing">annealed</a> to overcome local minima.<sup id="cite_ref-samish11_12-1" class="reference"><a href="#cite_note-samish11-12"><span class="cite-bracket">[</span>12<span class="cite-bracket">]</span></a></sup> </p> <div class="mw-heading mw-heading4"><h4 id="FASTER">FASTER</h4><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Protein_design&action=edit&section=17" title="Edit section: FASTER"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>The FASTER algorithm uses a combination of deterministic and stochastic criteria to optimize amino acid sequences. FASTER first uses DEE to eliminate rotamers that are not part of the optimal solution. Then, a series of iterative steps optimize the rotamer assignment.<sup id="cite_ref-34" class="reference"><a href="#cite_note-34"><span class="cite-bracket">[</span>34<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-35" class="reference"><a href="#cite_note-35"><span class="cite-bracket">[</span>35<span class="cite-bracket">]</span></a></sup> </p> <div class="mw-heading mw-heading4"><h4 id="Belief_propagation">Belief propagation</h4><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Protein_design&action=edit&section=18" title="Edit section: Belief propagation"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>In <a href="/wiki/Belief_propagation" title="Belief propagation">belief propagation</a> for protein design, the algorithm exchanges messages that describe the <i>belief</i> that each residue has about the probability of each rotamer in neighboring residues. The algorithm updates messages on every iteration and iterates until convergence or until a fixed number of iterations. Convergence is not guaranteed in protein design. The message <var>m</var><sub><var>i→ j</var></sub><var>(r<sub>j</sub></var> that a residue <var>i</var> sends to every rotamer <var>(r<sub>j</sub></var> at neighboring residue <var>j</var> is defined as: </p> <dl><dd><span class="mwe-math-element"><span class="mwe-math-mathml-inline mwe-math-mathml-a11y" style="display: none;"><math xmlns="http://www.w3.org/1998/Math/MathML" alttext="{\displaystyle m_{i\to j}(r_{j})=\max _{r_{i}}{\Big (}e^{\frac {-E_{i}(r_{i})-E_{ij}(r_{i},r_{j})}{T}}{\Big )}\prod _{k\in N(i)\backslash j}m_{k\to i(r_{i})}}"> <semantics> <mrow class="MJX-TeXAtom-ORD"> <mstyle displaystyle="true" scriptlevel="0"> <msub> <mi>m</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> <mo stretchy="false">→</mo> <mi>j</mi> </mrow> </msub> <mo stretchy="false">(</mo> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>j</mi> </mrow> </msub> <mo stretchy="false">)</mo> <mo>=</mo> <munder> <mo movablelimits="true" form="prefix">max</mo> <mrow class="MJX-TeXAtom-ORD"> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> </mrow> </msub> </mrow> </munder> <mrow class="MJX-TeXAtom-ORD"> <mrow class="MJX-TeXAtom-ORD"> <mo maxsize="1.623em" minsize="1.623em">(</mo> </mrow> </mrow> <msup> <mi>e</mi> <mrow class="MJX-TeXAtom-ORD"> <mfrac> <mrow> <mo>−</mo> <msub> <mi>E</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> </mrow> </msub> <mo stretchy="false">(</mo> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> </mrow> </msub> <mo stretchy="false">)</mo> <mo>−</mo> <msub> <mi>E</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> <mi>j</mi> </mrow> </msub> <mo stretchy="false">(</mo> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> </mrow> </msub> <mo>,</mo> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>j</mi> </mrow> </msub> <mo stretchy="false">)</mo> </mrow> <mi>T</mi> </mfrac> </mrow> </msup> <mrow class="MJX-TeXAtom-ORD"> <mrow class="MJX-TeXAtom-ORD"> <mo maxsize="1.623em" minsize="1.623em">)</mo> </mrow> </mrow> <munder> <mo>∏</mo> <mrow class="MJX-TeXAtom-ORD"> <mi>k</mi> <mo>∈</mo> <mi>N</mi> <mo stretchy="false">(</mo> <mi>i</mi> <mo stretchy="false">)</mo> <mi class="MJX-variant" mathvariant="normal">∖</mi> <mi>j</mi> </mrow> </munder> <msub> <mi>m</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>k</mi> <mo stretchy="false">→</mo> <mi>i</mi> <mo stretchy="false">(</mo> <msub> <mi>r</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>i</mi> </mrow> </msub> <mo stretchy="false">)</mo> </mrow> </msub> </mstyle> </mrow> <annotation encoding="application/x-tex">{\displaystyle m_{i\to j}(r_{j})=\max _{r_{i}}{\Big (}e^{\frac {-E_{i}(r_{i})-E_{ij}(r_{i},r_{j})}{T}}{\Big )}\prod _{k\in N(i)\backslash j}m_{k\to i(r_{i})}}</annotation> </semantics> </math></span><img src="https://wikimedia.org/api/rest_v1/media/math/render/svg/6901c80b4ecf02a7b7d8bab6a2d56097b9e41326" class="mwe-math-fallback-image-inline mw-invert skin-invert" aria-hidden="true" style="vertical-align: -3.505ex; width:49.094ex; height:7.509ex;" alt="{\displaystyle m_{i\to j}(r_{j})=\max _{r_{i}}{\Big (}e^{\frac {-E_{i}(r_{i})-E_{ij}(r_{i},r_{j})}{T}}{\Big )}\prod _{k\in N(i)\backslash j}m_{k\to i(r_{i})}}"></span></dd></dl> <p>Both max-product and sum-product belief propagation have been used to optimize protein design. </p> <div class="mw-heading mw-heading2"><h2 id="Applications_and_examples_of_designed_proteins">Applications and examples of designed proteins</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Protein_design&action=edit&section=19" title="Edit section: Applications and examples of designed proteins"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <div class="mw-heading mw-heading3"><h3 id="Enzyme_design">Enzyme design</h3><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Protein_design&action=edit&section=20" title="Edit section: Enzyme design"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>The design of new <a href="/wiki/Enzyme" title="Enzyme">enzymes</a> is a use of protein design with huge bioengineering and biomedical applications. In general, designing a protein structure can be different from designing an enzyme, because the design of enzymes must consider many states involved in the <a href="/wiki/Enzyme_catalysis" title="Enzyme catalysis">catalytic mechanism</a>. However protein design is a prerequisite of <i>de novo</i> enzyme design because, at the very least, the design of catalysts requires a scaffold in which the catalytic mechanism can be inserted.<sup id="cite_ref-baker10_36-0" class="reference"><a href="#cite_note-baker10-36"><span class="cite-bracket">[</span>36<span class="cite-bracket">]</span></a></sup> </p><p>Great progress in <i>de novo</i> enzyme design, and redesign, was made in the first decade of the 21st century. In three major studies, David Baker and coworkers <i>de novo</i> designed enzymes for the retro-<a href="/wiki/Aldol_reaction" title="Aldol reaction">aldol reaction</a>,<sup id="cite_ref-jiang08_37-0" class="reference"><a href="#cite_note-jiang08-37"><span class="cite-bracket">[</span>37<span class="cite-bracket">]</span></a></sup> a Kemp-elimination reaction,<sup id="cite_ref-roth08_38-0" class="reference"><a href="#cite_note-roth08-38"><span class="cite-bracket">[</span>38<span class="cite-bracket">]</span></a></sup> and for the <a href="/wiki/Diels-Alder_reaction" class="mw-redirect" title="Diels-Alder reaction">Diels-Alder reaction</a>.<sup id="cite_ref-39" class="reference"><a href="#cite_note-39"><span class="cite-bracket">[</span>39<span class="cite-bracket">]</span></a></sup> Furthermore, Stephen Mayo and coworkers developed an iterative method to design the most efficient known enzyme for the Kemp-elimination reaction.<sup id="cite_ref-40" class="reference"><a href="#cite_note-40"><span class="cite-bracket">[</span>40<span class="cite-bracket">]</span></a></sup> Also, in the laboratory of <a href="/wiki/Bruce_Donald" title="Bruce Donald">Bruce Donald</a>, computational protein design was used to switch the specificity of one of the <a href="/wiki/Protein_domain" title="Protein domain">protein domains</a> of the <a href="/wiki/Nonribosomal_peptide" title="Nonribosomal peptide">nonribosomal peptide synthetase</a> that produces <a href="/wiki/Gramicidin_S" title="Gramicidin S">Gramicidin S</a>, from its natural substrate <a href="/wiki/Phenylalanine" title="Phenylalanine">phenylalanine</a> to other noncognate substrates including charged amino acids; the redesigned enzymes had activities close to those of the wild-type.<sup id="cite_ref-chen09_41-0" class="reference"><a href="#cite_note-chen09-41"><span class="cite-bracket">[</span>41<span class="cite-bracket">]</span></a></sup> </p> <div class="mw-heading mw-heading3"><h3 id="Semi-rational_design">Semi-rational design</h3><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Protein_design&action=edit&section=21" title="Edit section: Semi-rational design"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>Semi-rational design is a purposeful modification method based on a certain understanding of the sequence, structure, and catalytic mechanism of enzymes. This method is between irrational design and rational design. It uses known information and means to perform evolutionary modification on the specific functions of the target enzyme. The characteristic of semi-rational design is that it does not rely solely on random mutation and screening, but combines the concept of directed evolution. It creates a library of random mutants with diverse sequences through <a href="/wiki/Mutagenesis" title="Mutagenesis">mutagenesis</a>, <a href="/wiki/Mutagenesis_(molecular_biology_technique)" title="Mutagenesis (molecular biology technique)">error-prone RCR</a>, <a href="/wiki/Recombinant_DNA" title="Recombinant DNA">DNA recombination</a>, and <a href="/wiki/Saturation_mutagenesis" title="Saturation mutagenesis">site-saturation mutagenesis</a>. At the same time, it uses the understanding of enzymes and design principles to purposefully screen out mutants with desired characteristics. </p><p>The methodology of semi-rational design emphasizes the in-depth understanding of enzymes and the control of the evolutionary process. It allows researchers to use known information to guide the evolutionary process, thereby improving efficiency and success rate. This method plays an important role in protein function modification because it can combine the advantages of irrational design and rational design, and can explore unknown space and use known knowledge for targeted modification. </p><p>Semi-rational design has a wide range of applications, including but not limited to enzyme optimization, modification of drug targets, evolution of biocatalysts, etc. Through this method, researchers can more effectively improve the functional properties of proteins to meet specific biotechnology or medical needs. Although this method has high requirements for information and technology and is relatively difficult to implement, with the development of computing technology and bioinformatics, the application prospects of semi-rational design in protein engineering are becoming more and more broad.<sup id="cite_ref-42" class="reference"><a href="#cite_note-42"><span class="cite-bracket">[</span>42<span class="cite-bracket">]</span></a></sup> </p> <div class="mw-heading mw-heading3"><h3 id="Design_for_affinity">Design for affinity</h3><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Protein_design&action=edit&section=22" title="Edit section: Design for affinity"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p><a href="/wiki/Protein%E2%80%93protein_interaction" title="Protein–protein interaction">Protein–protein interactions</a> are involved in most biotic processes. Many of the hardest-to-treat diseases, such as <a href="/wiki/Alzheimer" class="mw-redirect" title="Alzheimer">Alzheimer</a>'s, many forms of <a href="/wiki/Cancer" title="Cancer">cancer</a> (e.g., <a href="/wiki/TP53" class="mw-redirect" title="TP53">TP53</a>), and human immunodeficiency virus (<a href="/wiki/HIV" title="HIV">HIV</a>) infection involve protein–protein interactions. Thus, to treat such diseases, it is desirable to design protein or protein-like therapeutics that bind one of the partners of the interaction and, thus, disrupt the disease-causing interaction. This requires designing protein-therapeutics for <i>affinity</i> toward its partner. </p><p>Protein–protein interactions can be designed using protein design algorithms because the principles that rule protein stability also rule protein–protein binding. Protein–protein interaction design, however, presents challenges not commonly present in protein design. One of the most important challenges is that, in general, the interfaces between proteins are more polar than protein cores, and binding involves a tradeoff between desolvation and hydrogen bond formation.<sup id="cite_ref-kuhlman2009_43-0" class="reference"><a href="#cite_note-kuhlman2009-43"><span class="cite-bracket">[</span>43<span class="cite-bracket">]</span></a></sup> To overcome this challenge, Bruce Tidor and coworkers developed a method to improve the affinity of antibodies by focusing on electrostatic contributions. They found that, for the antibodies designed in the study, reducing the desolvation costs of the residues in the interface increased the affinity of the binding pair.<sup id="cite_ref-kuhlman2009_43-1" class="reference"><a href="#cite_note-kuhlman2009-43"><span class="cite-bracket">[</span>43<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-44" class="reference"><a href="#cite_note-44"><span class="cite-bracket">[</span>44<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-45" class="reference"><a href="#cite_note-45"><span class="cite-bracket">[</span>45<span class="cite-bracket">]</span></a></sup> </p> <div class="mw-heading mw-heading4"><h4 id="Scoring_binding_predictions">Scoring binding predictions</h4><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Protein_design&action=edit&section=23" title="Edit section: Scoring binding predictions"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>Protein design energy functions must be adapted to score binding predictions because binding involves a trade-off between the lowest-<a href="/wiki/Thermodynamic_free_energy" title="Thermodynamic free energy">energy</a> conformations of the free proteins (<var>E<sub>P</sub></var> and <var>E<sub>L</sub></var>) and the lowest-energy conformation of the bound complex (<var>E<sub>PL</sub></var>): </p> <dl><dd><span class="mwe-math-element"><span class="mwe-math-mathml-inline mwe-math-mathml-a11y" style="display: none;"><math xmlns="http://www.w3.org/1998/Math/MathML" alttext="{\displaystyle \Delta _{G}=E_{PL}-E_{P}-E_{L}}"> <semantics> <mrow class="MJX-TeXAtom-ORD"> <mstyle displaystyle="true" scriptlevel="0"> <msub> <mi mathvariant="normal">Δ</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>G</mi> </mrow> </msub> <mo>=</mo> <msub> <mi>E</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>P</mi> <mi>L</mi> </mrow> </msub> <mo>−</mo> <msub> <mi>E</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>P</mi> </mrow> </msub> <mo>−</mo> <msub> <mi>E</mi> <mrow class="MJX-TeXAtom-ORD"> <mi>L</mi> </mrow> </msub> </mstyle> </mrow> <annotation encoding="application/x-tex">{\displaystyle \Delta _{G}=E_{PL}-E_{P}-E_{L}}</annotation> </semantics> </math></span><img src="https://wikimedia.org/api/rest_v1/media/math/render/svg/29829ed769c32fa0f5ba34469601f7d0745a7718" class="mwe-math-fallback-image-inline mw-invert skin-invert" aria-hidden="true" style="vertical-align: -0.671ex; width:22.788ex; height:2.509ex;" alt="{\displaystyle \Delta _{G}=E_{PL}-E_{P}-E_{L}}"></span>.</dd></dl> <p>The K* algorithm approximates the binding constant of the algorithm by including conformational entropy into the free energy calculation. The K* algorithm considers only the lowest-energy conformations of the free and bound complexes (denoted by the sets <var>P</var>, <var>L</var>, and <var>PL</var>) to approximate the partition functions of each complex:<sup id="cite_ref-donald10_14-5" class="reference"><a href="#cite_note-donald10-14"><span class="cite-bracket">[</span>14<span class="cite-bracket">]</span></a></sup> </p> <dl><dd><span class="mwe-math-element"><span class="mwe-math-mathml-inline mwe-math-mathml-a11y" style="display: none;"><math xmlns="http://www.w3.org/1998/Math/MathML" alttext="{\displaystyle K^{*}={\frac {\sum \limits _{x\in PL}e^{-E(x)/RT}}{\sum \limits _{x\in P}e^{-E(x)/RT}\sum \limits _{x\in L}e^{-E(x)/RT}}}}"> <semantics> <mrow class="MJX-TeXAtom-ORD"> <mstyle displaystyle="true" scriptlevel="0"> <msup> <mi>K</mi> <mrow class="MJX-TeXAtom-ORD"> <mo>∗</mo> </mrow> </msup> <mo>=</mo> <mrow class="MJX-TeXAtom-ORD"> <mfrac> <mrow> <munder> <mo movablelimits="false">∑</mo> <mrow class="MJX-TeXAtom-ORD"> <mi>x</mi> <mo>∈</mo> <mi>P</mi> <mi>L</mi> </mrow> </munder> <msup> <mi>e</mi> <mrow class="MJX-TeXAtom-ORD"> <mo>−</mo> <mi>E</mi> <mo stretchy="false">(</mo> <mi>x</mi> <mo stretchy="false">)</mo> <mrow class="MJX-TeXAtom-ORD"> <mo>/</mo> </mrow> <mi>R</mi> <mi>T</mi> </mrow> </msup> </mrow> <mrow> <munder> <mo movablelimits="false">∑</mo> <mrow class="MJX-TeXAtom-ORD"> <mi>x</mi> <mo>∈</mo> <mi>P</mi> </mrow> </munder> <msup> <mi>e</mi> <mrow class="MJX-TeXAtom-ORD"> <mo>−</mo> <mi>E</mi> <mo stretchy="false">(</mo> <mi>x</mi> <mo stretchy="false">)</mo> <mrow class="MJX-TeXAtom-ORD"> <mo>/</mo> </mrow> <mi>R</mi> <mi>T</mi> </mrow> </msup> <munder> <mo movablelimits="false">∑</mo> <mrow class="MJX-TeXAtom-ORD"> <mi>x</mi> <mo>∈</mo> <mi>L</mi> </mrow> </munder> <msup> <mi>e</mi> <mrow class="MJX-TeXAtom-ORD"> <mo>−</mo> <mi>E</mi> <mo stretchy="false">(</mo> <mi>x</mi> <mo stretchy="false">)</mo> <mrow class="MJX-TeXAtom-ORD"> <mo>/</mo> </mrow> <mi>R</mi> <mi>T</mi> </mrow> </msup> </mrow> </mfrac> </mrow> </mstyle> </mrow> <annotation encoding="application/x-tex">{\displaystyle K^{*}={\frac {\sum \limits _{x\in PL}e^{-E(x)/RT}}{\sum \limits _{x\in P}e^{-E(x)/RT}\sum \limits _{x\in L}e^{-E(x)/RT}}}}</annotation> </semantics> </math></span><img src="https://wikimedia.org/api/rest_v1/media/math/render/svg/200efac14a130637fa418c4c678007668e8a9ef8" class="mwe-math-fallback-image-inline mw-invert skin-invert" aria-hidden="true" style="vertical-align: -4.671ex; width:33.262ex; height:10.676ex;" alt="{\displaystyle K^{*}={\frac {\sum \limits _{x\in PL}e^{-E(x)/RT}}{\sum \limits _{x\in P}e^{-E(x)/RT}\sum \limits _{x\in L}e^{-E(x)/RT}}}}"></span></dd></dl> <div class="mw-heading mw-heading3"><h3 id="Design_for_specificity">Design for specificity</h3><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Protein_design&action=edit&section=24" title="Edit section: Design for specificity"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>The design of protein–protein interactions must be highly specific because proteins can interact with a large number of proteins; successful design requires selective binders. Thus, protein design algorithms must be able to distinguish between on-target (or <i>positive design</i>) and off-target binding (or <i>negative design</i>).<sup id="cite_ref-richardson1989_2-5" class="reference"><a href="#cite_note-richardson1989-2"><span class="cite-bracket">[</span>2<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-kuhlman2009_43-2" class="reference"><a href="#cite_note-kuhlman2009-43"><span class="cite-bracket">[</span>43<span class="cite-bracket">]</span></a></sup> One of the most prominent examples of design for specificity is the design of specific <a href="/wiki/BZIP_domain" title="BZIP domain">bZIP</a>-binding peptides by Amy Keating and coworkers for 19 out of the 20 bZIP families; 8 of these peptides were specific for their intended partner over competing peptides.<sup id="cite_ref-kuhlman2009_43-3" class="reference"><a href="#cite_note-kuhlman2009-43"><span class="cite-bracket">[</span>43<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-schreiber11_46-0" class="reference"><a href="#cite_note-schreiber11-46"><span class="cite-bracket">[</span>46<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-47" class="reference"><a href="#cite_note-47"><span class="cite-bracket">[</span>47<span class="cite-bracket">]</span></a></sup> Further, positive and negative design was also used by Anderson and coworkers to predict mutations in the active site of a drug target that conferred resistance to a new drug; positive design was used to maintain wild-type activity, while negative design was used to disrupt binding of the drug.<sup id="cite_ref-frey10_48-0" class="reference"><a href="#cite_note-frey10-48"><span class="cite-bracket">[</span>48<span class="cite-bracket">]</span></a></sup> Recent computational redesign by Costas Maranas and coworkers was also capable of experimentally switching the <a href="/wiki/Cofactor_(biochemistry)" title="Cofactor (biochemistry)">cofactor</a> specificity of <i>Candida boidinii</i> xylose reductase from <a href="/wiki/Nicotinamide_adenine_dinucleotide_phosphate" title="Nicotinamide adenine dinucleotide phosphate">NADPH</a> to <a href="/wiki/Nicotinamide_adenine_dinucleotide" title="Nicotinamide adenine dinucleotide">NADH</a>.<sup id="cite_ref-khoury_49-0" class="reference"><a href="#cite_note-khoury-49"><span class="cite-bracket">[</span>49<span class="cite-bracket">]</span></a></sup> </p> <div class="mw-heading mw-heading3"><h3 id="Protein_resurfacing">Protein resurfacing</h3><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Protein_design&action=edit&section=25" title="Edit section: Protein resurfacing"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>Protein resurfacing consists of designing a protein's surface while preserving the overall fold, core, and boundary regions of the protein intact. Protein resurfacing is especially useful to alter the binding of a protein to other proteins. One of the most important applications of protein resurfacing was the design of the RSC3 probe to select broadly neutralizing HIV antibodies at the NIH Vaccine Research Center. First, residues outside of the binding interface between the gp120 HIV envelope protein and the formerly discovered b12-antibody were selected to be designed. Then, the sequence spaced was selected based on evolutionary information, solubility, similarity with the wild-type, and other considerations. Then the RosettaDesign software was used to find optimal sequences in the selected sequence space. RSC3 was later used to discover the broadly neutralizing antibody VRC01 in the serum of a long-term HIV-infected non-progressor individual.<sup id="cite_ref-50" class="reference"><a href="#cite_note-50"><span class="cite-bracket">[</span>50<span class="cite-bracket">]</span></a></sup> </p> <div class="mw-heading mw-heading3"><h3 id="Design_of_globular_proteins">Design of globular proteins</h3><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Protein_design&action=edit&section=26" title="Edit section: Design of globular proteins"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p><a href="/wiki/Globular_protein" title="Globular protein">Globular proteins</a> are proteins that contain a hydrophobic core and a hydrophilic surface. Globular proteins often assume a stable structure, unlike <a href="/wiki/Fibrous_protein" title="Fibrous protein">fibrous proteins</a>, which have multiple conformations. The three-dimensional structure of globular proteins is typically easier to determine through <a href="/wiki/X-ray_crystallography" title="X-ray crystallography">X-ray crystallography</a> and <a href="/wiki/Nuclear_magnetic_resonance" title="Nuclear magnetic resonance">nuclear magnetic resonance</a> than both fibrous proteins and <a href="/wiki/Membrane_protein" title="Membrane protein">membrane proteins</a>, which makes globular proteins more attractive for protein design than the other types of proteins. Most successful protein designs have involved globular proteins. Both <a href="#Sequence_space">RSD-1</a>, and <a href="#Target_structure">Top7</a> were <i>de novo</i> designs of globular proteins. Five more protein structures were designed, synthesized, and verified in 2012 by the Baker group. These new proteins serve no biotic function, but the structures are intended to act as building-blocks that can be expanded to incorporate functional active sites. The structures were found computationally by using new heuristics based on analyzing the connecting loops between parts of the sequence that specify secondary structures.<sup id="cite_ref-51" class="reference"><a href="#cite_note-51"><span class="cite-bracket">[</span>51<span class="cite-bracket">]</span></a></sup> </p> <div class="mw-heading mw-heading3"><h3 id="Design_of_membrane_proteins">Design of membrane proteins</h3><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Protein_design&action=edit&section=27" title="Edit section: Design of membrane proteins"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>Several transmembrane proteins have been successfully designed,<sup id="cite_ref-52" class="reference"><a href="#cite_note-52"><span class="cite-bracket">[</span>52<span class="cite-bracket">]</span></a></sup> along with many other membrane-associated peptides and proteins.<sup id="cite_ref-53" class="reference"><a href="#cite_note-53"><span class="cite-bracket">[</span>53<span class="cite-bracket">]</span></a></sup> Recently, Costas Maranas and his coworkers developed an automated tool<sup id="cite_ref-54" class="reference"><a href="#cite_note-54"><span class="cite-bracket">[</span>54<span class="cite-bracket">]</span></a></sup> to redesign the pore size of Outer Membrane Porin Type-F (OmpF) from <i>E.coli</i> to any desired sub-nm size and assembled them in membranes to perform precise angstrom scale separation. </p> <div class="mw-heading mw-heading3"><h3 id="Other_applications">Other applications</h3><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Protein_design&action=edit&section=28" title="Edit section: Other applications"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>One of the most desirable uses for protein design is for <a href="/wiki/Biosensor" title="Biosensor">biosensors</a>, proteins that will sense the presence of specific compounds. Some attempts in the design of biosensors include sensors for unnatural molecules including <a href="/wiki/TNT" title="TNT">TNT</a>.<sup id="cite_ref-55" class="reference"><a href="#cite_note-55"><span class="cite-bracket">[</span>55<span class="cite-bracket">]</span></a></sup> More recently, Kuhlman and coworkers designed a biosensor of the <a href="/wiki/P21_activated_kinase" class="mw-redirect" title="P21 activated kinase">PAK1</a>.<sup id="cite_ref-56" class="reference"><a href="#cite_note-56"><span class="cite-bracket">[</span>56<span class="cite-bracket">]</span></a></sup> </p><p>In a sense, protein design is a subset of <a href="/wiki/Circuit_design" title="Circuit design">battery design</a>.<sup class="noprint Inline-Template" style="white-space:nowrap;">[<i><a href="/wiki/Wikipedia:Please_clarify" title="Wikipedia:Please clarify"><span title="The text near this tag needs further explanation. (April 2022)">further explanation needed</span></a></i>]</sup> </p> <div class="mw-heading mw-heading2"><h2 id="See_also">See also</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Protein_design&action=edit&section=29" title="Edit section: See also"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <ul><li><a href="/wiki/Protein_engineering" title="Protein engineering">Protein engineering</a> – Bioengineering process</li> <li><a href="/wiki/Molecular_design_software" title="Molecular design software">Molecular design software</a> – CAD software for molecular-level engineering, modelling, and analysis<span style="display:none" class="category-wikidata-fallback-annotation">Pages displaying wikidata descriptions as a fallback</span> <ul><li><a href="/wiki/Comparison_of_software_for_molecular_mechanics_modeling" title="Comparison of software for molecular mechanics modeling">Comparison of software for molecular mechanics modeling</a></li> <li><a href="/wiki/Protein_structure_prediction_software" class="mw-redirect" title="Protein structure prediction software">Protein structure prediction software</a></li></ul></li> <li><a href="/wiki/Synthetic_biology" title="Synthetic biology">Synthetic biology</a> – Interdisciplinary branch of biology and engineering</li></ul> <div class="mw-heading mw-heading2"><h2 id="References">References</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Protein_design&action=edit&section=30" title="Edit section: References"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <style data-mw-deduplicate="TemplateStyles:r1239543626">.mw-parser-output .reflist{margin-bottom:0.5em;list-style-type:decimal}@media screen{.mw-parser-output .reflist{font-size:90%}}.mw-parser-output .reflist .references{font-size:100%;margin-bottom:0;list-style-type:inherit}.mw-parser-output .reflist-columns-2{column-width:30em}.mw-parser-output .reflist-columns-3{column-width:25em}.mw-parser-output .reflist-columns{margin-top:0.3em}.mw-parser-output .reflist-columns ol{margin-top:0}.mw-parser-output .reflist-columns li{page-break-inside:avoid;break-inside:avoid-column}.mw-parser-output .reflist-upper-alpha{list-style-type:upper-alpha}.mw-parser-output .reflist-upper-roman{list-style-type:upper-roman}.mw-parser-output .reflist-lower-alpha{list-style-type:lower-alpha}.mw-parser-output .reflist-lower-greek{list-style-type:lower-greek}.mw-parser-output .reflist-lower-roman{list-style-type:lower-roman}</style><div class="reflist reflist-columns references-column-width" style="column-width: 30em;"> <ol class="references"> <li id="cite_note-1"><span class="mw-cite-backlink"><b><a href="#cite_ref-1">^</a></b></span> <span class="reference-text"><style data-mw-deduplicate="TemplateStyles:r1238218222">.mw-parser-output cite.citation{font-style:inherit;word-wrap:break-word}.mw-parser-output .citation q{quotes:"\"""\"""'""'"}.mw-parser-output .citation:target{background-color:rgba(0,127,255,0.133)}.mw-parser-output .id-lock-free.id-lock-free a{background:url("//upload.wikimedia.org/wikipedia/commons/6/65/Lock-green.svg")right 0.1em center/9px no-repeat}.mw-parser-output .id-lock-limited.id-lock-limited a,.mw-parser-output .id-lock-registration.id-lock-registration a{background:url("//upload.wikimedia.org/wikipedia/commons/d/d6/Lock-gray-alt-2.svg")right 0.1em center/9px no-repeat}.mw-parser-output .id-lock-subscription.id-lock-subscription a{background:url("//upload.wikimedia.org/wikipedia/commons/a/aa/Lock-red-alt-2.svg")right 0.1em center/9px no-repeat}.mw-parser-output .cs1-ws-icon a{background:url("//upload.wikimedia.org/wikipedia/commons/4/4c/Wikisource-logo.svg")right 0.1em center/12px no-repeat}body:not(.skin-timeless):not(.skin-minerva) .mw-parser-output .id-lock-free a,body:not(.skin-timeless):not(.skin-minerva) .mw-parser-output .id-lock-limited a,body:not(.skin-timeless):not(.skin-minerva) .mw-parser-output .id-lock-registration a,body:not(.skin-timeless):not(.skin-minerva) .mw-parser-output .id-lock-subscription a,body:not(.skin-timeless):not(.skin-minerva) .mw-parser-output .cs1-ws-icon a{background-size:contain;padding:0 1em 0 0}.mw-parser-output .cs1-code{color:inherit;background:inherit;border:none;padding:inherit}.mw-parser-output .cs1-hidden-error{display:none;color:var(--color-error,#d33)}.mw-parser-output .cs1-visible-error{color:var(--color-error,#d33)}.mw-parser-output .cs1-maint{display:none;color:#085;margin-left:0.3em}.mw-parser-output .cs1-kern-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right{padding-right:0.2em}.mw-parser-output .citation .mw-selflink{font-weight:inherit}@media screen{.mw-parser-output .cs1-format{font-size:95%}html.skin-theme-clientpref-night .mw-parser-output .cs1-maint{color:#18911f}}@media screen and (prefers-color-scheme:dark){html.skin-theme-clientpref-os .mw-parser-output .cs1-maint{color:#18911f}}</style><cite id="CITEREFKorendovych2018" class="citation news cs1">Korendovych, Ivan (March 19, 2018). <a rel="nofollow" class="external text" href="https://plan.core-apps.com/acsnola2018/abstract/3b00ff75f22454219cca274e14edadf8">"Minimalist design of peptide and protein catalysts"</a>. 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"Computational design of receptor and sensor proteins with novel functions". <i><a href="/wiki/Nature_(journal)" title="Nature (journal)">Nature</a></i>. <b>423</b> (6936): <span class="nowrap">185–</span>190. <a href="/wiki/Bibcode_(identifier)" class="mw-redirect" title="Bibcode (identifier)">Bibcode</a>:<a rel="nofollow" class="external text" href="https://ui.adsabs.harvard.edu/abs/2003Natur.423..185L">2003Natur.423..185L</a>. <a href="/wiki/Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1038%2Fnature01556">10.1038/nature01556</a>. <a href="/wiki/PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/12736688">12736688</a>. <a href="/wiki/S2CID_(identifier)" class="mw-redirect" title="S2CID (identifier)">S2CID</a> <a rel="nofollow" class="external text" href="https://api.semanticscholar.org/CorpusID:4387641">4387641</a>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=Nature&rft.atitle=Computational+design+of+receptor+and+sensor+proteins+with+novel+functions&rft.volume=423&rft.issue=6936&rft.pages=%3Cspan+class%3D%22nowrap%22%3E185-%3C%2Fspan%3E190&rft.date=2003&rft_id=info%3Adoi%2F10.1038%2Fnature01556&rft_id=https%3A%2F%2Fapi.semanticscholar.org%2FCorpusID%3A4387641%23id-name%3DS2CID&rft_id=info%3Apmid%2F12736688&rft_id=info%3Abibcode%2F2003Natur.423..185L&rft.aulast=Looger&rft.aufirst=Loren+L.&rft.au=Dwyer%2C+Mary+A.&rft.au=Smith%2C+James+J.&rft.au=Hellinga%2C+Homme+W.&rfr_id=info%3Asid%2Fen.wikipedia.org%3AProtein+design" class="Z3988"></span></span> </li> <li id="cite_note-56"><span class="mw-cite-backlink"><b><a href="#cite_ref-56">^</a></b></span> <span class="reference-text"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222"><cite id="CITEREFJhaWu,_YIZawistowski,_JSMacNevin,_C2011" class="citation journal cs1">Jha, RK; Wu, YI; Zawistowski, JS; MacNevin, C; Hahn, KM; Kuhlman, B (October 21, 2011). <a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3202338">"Redesign of the PAK1 autoinhibitory domain for enhanced stability and affinity in biosensor applications"</a>. <i>Journal of Molecular Biology</i>. <b>413</b> (2): <span class="nowrap">513–</span>22. <a href="/wiki/Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1016%2Fj.jmb.2011.08.022">10.1016/j.jmb.2011.08.022</a>. <a href="/wiki/PMC_(identifier)" class="mw-redirect" title="PMC (identifier)">PMC</a> <span class="id-lock-free" title="Freely accessible"><a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3202338">3202338</a></span>. <a href="/wiki/PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/21888918">21888918</a>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=Journal+of+Molecular+Biology&rft.atitle=Redesign+of+the+PAK1+autoinhibitory+domain+for+enhanced+stability+and+affinity+in+biosensor+applications.&rft.volume=413&rft.issue=2&rft.pages=%3Cspan+class%3D%22nowrap%22%3E513-%3C%2Fspan%3E22&rft.date=2011-10-21&rft_id=https%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fpmc%2Farticles%2FPMC3202338%23id-name%3DPMC&rft_id=info%3Apmid%2F21888918&rft_id=info%3Adoi%2F10.1016%2Fj.jmb.2011.08.022&rft.aulast=Jha&rft.aufirst=RK&rft.au=Wu%2C+YI&rft.au=Zawistowski%2C+JS&rft.au=MacNevin%2C+C&rft.au=Hahn%2C+KM&rft.au=Kuhlman%2C+B&rft_id=https%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fpmc%2Farticles%2FPMC3202338&rfr_id=info%3Asid%2Fen.wikipedia.org%3AProtein+design" class="Z3988"></span></span> </li> </ol></div> <div class="mw-heading mw-heading2"><h2 id="Further_reading">Further reading</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Protein_design&action=edit&section=31" title="Edit section: Further reading"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <ul><li><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222"><cite id="CITEREFDonald2011" class="citation book cs1"><a href="/wiki/Bruce_Donald" title="Bruce Donald">Donald, Bruce R.</a> (2011). <a rel="nofollow" class="external text" href="https://books.google.com/books?id=GSw3AgAAQBAJ"><i>Algorithms in Structural Molecular Biology</i></a>. Computational Molecular Biology. Cambridge, MA: The MIT Press. <a href="/wiki/ISBN_(identifier)" class="mw-redirect" title="ISBN (identifier)">ISBN</a> <a href="/wiki/Special:BookSources/9780262015592" title="Special:BookSources/9780262015592"><bdi>9780262015592</bdi></a>. <a href="/wiki/OCLC_(identifier)" class="mw-redirect" title="OCLC (identifier)">OCLC</a> <a rel="nofollow" class="external text" href="https://search.worldcat.org/oclc/1200909148">1200909148</a>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=book&rft.btitle=Algorithms+in+Structural+Molecular+Biology&rft.place=Cambridge%2C+MA&rft.series=Computational+Molecular+Biology&rft.pub=The+MIT+Press&rft.date=2011&rft_id=info%3Aoclcnum%2F1200909148&rft.isbn=9780262015592&rft.aulast=Donald&rft.aufirst=Bruce+R.&rft_id=https%3A%2F%2Fbooks.google.com%2Fbooks%3Fid%3DGSw3AgAAQBAJ&rfr_id=info%3Asid%2Fen.wikipedia.org%3AProtein+design" class="Z3988"></span></li> <li><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222"><cite id="CITEREFJinKambaraSasakawaTamura2003" class="citation journal cs1">Jin, Wenzhen; Kambara, Ohki; Sasakawa, Hiroaki; Tamura, Atsuo & Takada, Shoji (May 2003). <a rel="nofollow" class="external text" href="https://doi.org/10.1016%2FS0969-2126%2803%2900075-3">"De Novo Design of Foldable Proteins with Smooth Folding Funnel: Automated Negative Design and Experimental Verification"</a>. <i>Structure</i>. <b>11</b> (5): <span class="nowrap">581–</span>590. <a href="/wiki/Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<span class="id-lock-free" title="Freely accessible"><a rel="nofollow" class="external text" href="https://doi.org/10.1016%2FS0969-2126%2803%2900075-3">10.1016/S0969-2126(03)00075-3</a></span>. <a href="/wiki/PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/12737823">12737823</a>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=Structure&rft.atitle=De+Novo+Design+of+Foldable+Proteins+with+Smooth+Folding+Funnel%3A+Automated+Negative+Design+and+Experimental+Verification&rft.volume=11&rft.issue=5&rft.pages=%3Cspan+class%3D%22nowrap%22%3E581-%3C%2Fspan%3E590&rft.date=2003-05&rft_id=info%3Adoi%2F10.1016%2FS0969-2126%2803%2900075-3&rft_id=info%3Apmid%2F12737823&rft.aulast=Jin&rft.aufirst=Wenzhen&rft.au=Kambara%2C+Ohki&rft.au=Sasakawa%2C+Hiroaki&rft.au=Tamura%2C+Atsuo&rft.au=Takada%2C+Shoji&rft_id=https%3A%2F%2Fdoi.org%2F10.1016%252FS0969-2126%252803%252900075-3&rfr_id=info%3Asid%2Fen.wikipedia.org%3AProtein+design" class="Z3988"></span></li> <li><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222"><cite id="CITEREFPokalaHandel2005" class="citation journal cs1">Pokala, Navin & Handel, Tracy M. (2005). "Energy Functions for Protein Design: Adjustment with Protein–Protein Complex Affinities, Models for the Unfolded State, and Negative Design of Solubility and Specificity". <i>Journal of Molecular Biology</i>. <b>347</b> (1): <span class="nowrap">203–</span>227. <a href="/wiki/Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1016%2Fj.jmb.2004.12.019">10.1016/j.jmb.2004.12.019</a>. <a href="/wiki/PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/15733929">15733929</a>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=Journal+of+Molecular+Biology&rft.atitle=Energy+Functions+for+Protein+Design%3A+Adjustment+with+Protein%E2%80%93Protein+Complex+Affinities%2C+Models+for+the+Unfolded+State%2C+and+Negative+Design+of+Solubility+and+Specificity&rft.volume=347&rft.issue=1&rft.pages=%3Cspan+class%3D%22nowrap%22%3E203-%3C%2Fspan%3E227&rft.date=2005&rft_id=info%3Adoi%2F10.1016%2Fj.jmb.2004.12.019&rft_id=info%3Apmid%2F15733929&rft.aulast=Pokala&rft.aufirst=Navin&rft.au=Handel%2C+Tracy+M.&rfr_id=info%3Asid%2Fen.wikipedia.org%3AProtein+design" class="Z3988"></span></li> <li><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222"><cite id="CITEREFSanderVriendBazanHorovitz1992" class="citation journal cs1">Sander, Chris; Vriend, Gerrit; Bazan, Fernando; Horovitz, Amnon; Nakamura, Haruki; Ribas, Luis; Finkelstein, Alexei V.; Lockhart, Andrew; Merkl, Rainer; et al. (February 1992). "Protein Design on Computers. Five New Proteins: Shpilka, Grendel, Fingerclasp, Leather and Aida". <i>Proteins: Structure, Function, and Bioinformatics</i>. <b>12</b> (2): <span class="nowrap">105–</span>110. <a href="/wiki/Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1002%2Fprot.340120203">10.1002/prot.340120203</a>. <a href="/wiki/PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/1603799">1603799</a>. <a href="/wiki/S2CID_(identifier)" class="mw-redirect" title="S2CID (identifier)">S2CID</a> <a rel="nofollow" class="external text" href="https://api.semanticscholar.org/CorpusID:38986245">38986245</a>.</cite><span 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abbr{color:var(--color-base)!important}}@media print{.mw-parser-output .navbar{display:none!important}}</style><div class="navbar plainlinks hlist navbar-mini"><ul><li class="nv-view"><a href="/wiki/Template:Biomolecular_structure" title="Template:Biomolecular structure"><abbr title="View this template">v</abbr></a></li><li class="nv-talk"><a href="/wiki/Template_talk:Biomolecular_structure" title="Template talk:Biomolecular structure"><abbr title="Discuss this template">t</abbr></a></li><li class="nv-edit"><a href="/wiki/Special:EditPage/Template:Biomolecular_structure" title="Special:EditPage/Template:Biomolecular structure"><abbr title="Edit this template">e</abbr></a></li></ul></div><div id="Biomolecular_structure102" style="font-size:114%;margin:0 4em"><a href="/wiki/Biomolecular_structure" title="Biomolecular structure">Biomolecular structure</a></div></th></tr><tr><th scope="row" class="navbox-group" style="background:lightblue;width:1%"><a href="/wiki/Protein_structure" title="Protein structure">Protein</a></th><td class="navbox-list-with-group navbox-list navbox-odd hlist" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Protein_primary_structure" title="Protein primary structure">Primary</a></li> <li><a href="/wiki/Protein_secondary_structure" title="Protein secondary structure">Secondary</a></li> <li><a href="/wiki/Protein_tertiary_structure" title="Protein tertiary structure">Tertiary</a></li> <li><a href="/wiki/Protein_quaternary_structure" title="Protein quaternary structure">Quaternary</a></li> <li><a href="/wiki/Protein_structure#Protein_structure_determination" title="Protein structure">Determination</a></li> <li><a href="/wiki/Protein_structure_prediction" title="Protein structure prediction">Prediction</a></li> <li><a class="mw-selflink selflink">Design</a></li> <li><a href="/wiki/Protein_thermodynamics" class="mw-redirect" title="Protein thermodynamics">Thermodynamics</a></li></ul> </div></td></tr><tr><th scope="row" class="navbox-group" style="background:lightblue;width:1%"><a href="/wiki/Nucleic_acid_structure" title="Nucleic acid structure">Nucleic acid</a></th><td class="navbox-list-with-group navbox-list navbox-even hlist" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Nucleic_acid_sequence" title="Nucleic acid sequence">Primary</a></li> <li><a href="/wiki/Nucleic_acid_secondary_structure" title="Nucleic acid secondary structure">Secondary</a></li> <li><a href="/wiki/Nucleic_acid_tertiary_structure" title="Nucleic acid tertiary structure">Tertiary</a></li> <li><a href="/wiki/Nucleic_acid_quaternary_structure" title="Nucleic acid quaternary structure">Quaternary</a></li> <li><a href="/wiki/Nucleic_acid_structure_determination" title="Nucleic acid structure determination">Determination</a></li> <li><a href="/wiki/Nucleic_acid_structure_prediction" title="Nucleic acid structure prediction">Prediction</a></li> <li><a href="/wiki/Nucleic_acid_design" title="Nucleic acid design">Design</a></li> <li><a href="/wiki/Nucleic_acid_thermodynamics" title="Nucleic acid thermodynamics">Thermodynamics</a></li></ul> </div></td></tr><tr><th scope="row" class="navbox-group" style="background:lightblue;width:1%">See also</th><td class="navbox-list-with-group navbox-list navbox-odd hlist" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Protein" title="Protein">Protein</a></li> <li><a href="/wiki/Protein_domain" title="Protein domain">Protein domain</a></li> <li><a href="/wiki/Protein_engineering" title="Protein engineering">Protein engineering</a></li> <li><a href="/wiki/Proteasome" title="Proteasome">Proteasome</a></li> <li><a href="/wiki/Nucleic_acid" title="Nucleic acid">Nucleic acid</a></li> <li><a href="/wiki/DNA" title="DNA">DNA</a></li> <li><a href="/wiki/RNA" title="RNA">RNA</a></li> <li><a href="/wiki/Structural_motif" title="Structural motif">Structural motif</a></li> <li><a href="/wiki/Nucleic_acid_double_helix" title="Nucleic acid double helix">Nucleic acid double helix</a></li></ul> </div></td></tr></tbody></table></div> <div class="navbox-styles"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1129693374"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1236075235"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1129693374"><style data-mw-deduplicate="TemplateStyles:r1239334494">@media screen{html.skin-theme-clientpref-night .mw-parser-output div:not(.notheme)>.tmp-color,html.skin-theme-clientpref-night .mw-parser-output p>.tmp-color,html.skin-theme-clientpref-night .mw-parser-output table:not(.notheme) .tmp-color{color:inherit!important}}@media screen and (prefers-color-scheme:dark){html.skin-theme-clientpref-os .mw-parser-output div:not(.notheme)>.tmp-color,html.skin-theme-clientpref-os .mw-parser-output p>.tmp-color,html.skin-theme-clientpref-os .mw-parser-output table:not(.notheme) .tmp-color{color:inherit!important}}</style><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1239334494"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1239334494"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1239334494"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1239334494"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1239334494"></div><div role="navigation" class="navbox" aria-labelledby="Design931" style="padding:3px"><table class="nowraplinks hlist mw-collapsible mw-collapsed navbox-inner" style="border-spacing:0;background:transparent;color:inherit"><tbody><tr><th scope="col" class="navbox-title" colspan="2"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1129693374"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1239400231"><div class="navbar plainlinks hlist navbar-mini"><ul><li class="nv-view"><a href="/wiki/Template:Design" title="Template:Design"><abbr title="View this template">v</abbr></a></li><li class="nv-talk"><a href="/wiki/Template_talk:Design" title="Template talk:Design"><abbr title="Discuss this template">t</abbr></a></li><li class="nv-edit"><a href="/wiki/Special:EditPage/Template:Design" title="Special:EditPage/Template:Design"><abbr title="Edit this template">e</abbr></a></li></ul></div><div id="Design931" style="font-size:114%;margin:0 4em"><a href="/wiki/Design" title="Design">Design</a></div></th></tr><tr><td class="navbox-abovebelow hlist" colspan="2"><div> <ul><li><a href="/wiki/Outline_of_design" title="Outline of design">Outline</a></li> <li><a href="/wiki/Designer" title="Designer">Designer</a></li></ul> </div></td></tr><tr><td colspan="2" class="navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em"></div><table class="nowraplinks mw-collapsible mw-collapsed navbox-subgroup" style="border-spacing:0"><tbody><tr><th scope="col" class="navbox-title" colspan="2"><div id="Disciplines931" style="font-size:114%;margin:0 4em">Disciplines</div></th></tr><tr><td colspan="2" class="navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em"></div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th scope="row" class="navbox-group" style="width:1%"><a href="/wiki/Communication_design" title="Communication design">Communication<br />design</a></th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Advertising" title="Advertising">Advertising</a></li> <li><a href="/wiki/Book_design" title="Book design">Book design</a></li> <li><a href="/wiki/Brand" title="Brand">Brand design</a></li> <li><a href="/wiki/Exhibit_design" title="Exhibit design">Exhibit design</a></li> <li><a href="/wiki/Film_title_design" title="Film title design">Film title design</a></li> <li><a href="/wiki/Graphic_design" title="Graphic design">Graphic design</a> <ul><li><a href="/wiki/Motion_graphic_design" title="Motion graphic design">Motion</a></li> <li><a href="/wiki/Postage_stamp_design" title="Postage stamp design">Postage stamp design</a></li> <li><a href="/wiki/Print_design" title="Print design">Print design</a></li></ul></li> <li><a href="/wiki/Illustration" title="Illustration">Illustration</a></li> <li><a href="/wiki/Information_design" title="Information design">Information design</a></li> <li><a href="/wiki/Instructional_design" title="Instructional design">Instructional design</a></li> <li><a href="/wiki/News_design" title="News design">News design</a></li> <li><a href="/wiki/Photography" title="Photography">Photography</a></li> <li><a href="/wiki/Retail_design" title="Retail design">Retail design</a></li> <li><a href="/wiki/Signage" title="Signage">Signage</a> / <a href="/wiki/Traffic_sign_design" title="Traffic sign design">Traffic sign design</a></li> <li><a href="/wiki/Typography" title="Typography">Typography</a> / <a href="/wiki/Type_design" title="Type design">Type design</a></li> <li><a href="/wiki/Video_design" title="Video design">Video design</a></li> <li><a href="/wiki/Visual_merchandising" title="Visual merchandising">Visual merchandising</a></li></ul> </div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%"><a href="/wiki/Environmental_design" title="Environmental design">Environmental<br />design</a></th><td class="navbox-list-with-group navbox-list navbox-even" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Architecture" title="Architecture">Architecture</a></li> <li><a href="/wiki/Architectural_lighting_design" title="Architectural lighting design">Architectural lighting design</a></li> <li><a href="/wiki/Building_design" title="Building design">Building design</a> <ul><li><a href="/wiki/Passive_solar_building_design" title="Passive solar building design">Passive solar</a></li></ul></li> <li><a href="/wiki/Ecological_design" title="Ecological design">Ecological design</a></li> <li><a href="/wiki/Environmental_impact_design" title="Environmental impact design">Environmental impact design</a></li> <li><a href="/wiki/Garden_design" title="Garden design">Garden design</a> <ul><li><a href="/wiki/Computer-aided_garden_design" title="Computer-aided garden design">Computer-aided</a></li></ul></li> <li><a href="/wiki/Healthy_community_design" title="Healthy community design">Healthy community design</a></li> <li><a href="/wiki/Hotel_design" title="Hotel design">Hotel design</a></li> <li><a href="/wiki/Interior_architecture" title="Interior architecture">Interior architecture</a></li> <li><a href="/wiki/Interior_design" title="Interior design">Interior design</a> <ul><li><a href="/wiki/Experiential_interior_design" title="Experiential interior design">EID</a></li></ul></li> <li><a href="/wiki/Keyline_design" title="Keyline design">Keyline design</a></li> <li><a href="/wiki/Landscape_architecture" title="Landscape architecture">Landscape architecture</a> <ul><li><a href="/wiki/Sustainable_landscape_architecture" title="Sustainable landscape architecture">Sustainable</a></li></ul></li> <li><a href="/wiki/Landscape_design" title="Landscape design">Landscape design</a></li> <li><a href="/wiki/Spatial_design" title="Spatial design">Spatial design</a></li> <li><a href="/wiki/Urban_design" title="Urban design">Urban design</a></li></ul> </div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%"><a href="/wiki/Industrial_design" title="Industrial design">Industrial<br />design</a></th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Automotive_design" title="Automotive design">Automotive design</a></li> <li><a href="/wiki/Automotive_suspension_design_process" title="Automotive suspension design process">Automotive suspension design</a></li> <li><a href="/wiki/CMF_design" title="CMF design">CMF design</a></li> <li><a href="/wiki/Corrugated_box_design" title="Corrugated box design">Corrugated box design</a></li> <li><a href="/wiki/Electric_guitar_design" title="Electric guitar design">Electric guitar design</a></li> <li><a href="/wiki/Furniture" title="Furniture">Furniture design</a> <ul><li><a href="/wiki/Sustainable_furniture_design" title="Sustainable furniture design">Sustainable</a></li></ul></li> <li><a href="/wiki/Hardware_interface_design" title="Hardware interface design">Hardware interface design</a></li> <li><a href="/wiki/Motorcycle_design" title="Motorcycle design">Motorcycle design</a></li> <li><a href="/wiki/Packaging_and_labeling" class="mw-redirect" title="Packaging and labeling">Packaging and labeling</a></li> <li><a href="/wiki/Photographic_lens_design" title="Photographic lens design">Photographic lens design</a></li> <li><a href="/wiki/Product_design" title="Product design">Product design</a></li> <li><a href="/wiki/Production_designer" title="Production designer">Production design</a></li> <li><a href="/wiki/Sensory_design" title="Sensory design">Sensory design</a></li> <li><a href="/wiki/Service_design" title="Service design">Service design</a></li></ul> </div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%"><a href="/wiki/Interaction_design" title="Interaction design">Interaction<br />design</a></th><td class="navbox-list-with-group navbox-list navbox-even" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Experience_design" class="mw-redirect" title="Experience design">Experience design</a> <ul><li><a href="/wiki/Employee_experience_design" title="Employee experience design">EED</a></li></ul></li> <li><a href="/wiki/Game_design" title="Game design">Game design</a> <ul><li><a href="/wiki/Level_(video_games)" title="Level (video games)">Level design</a></li> <li><a href="/wiki/Video_game_design" title="Video game design">Video game design</a></li></ul></li> <li><a href="/wiki/Hardware_interface_design" title="Hardware interface design">Hardware interface design</a></li> <li><a href="/wiki/Icon_design" title="Icon design">Icon design</a></li> <li><a href="/wiki/Immersive_design" title="Immersive design">Immersive design</a></li> <li><a href="/wiki/Information_design" title="Information design">Information design</a></li> <li><a href="/wiki/Sonic_interaction_design" title="Sonic interaction design">Sonic interaction design</a></li> <li><a href="/wiki/User_experience_design" title="User experience design">User experience design</a></li> <li><a href="/wiki/User_interface_design" title="User interface design">User interface design</a></li> <li><a href="/wiki/Web_design" title="Web design">Web design</a></li></ul> </div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%">Other<br /><a href="/wiki/Applied_arts" title="Applied arts">applied arts</a></th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Public_art" title="Public art">Public art design</a></li> <li><a href="/wiki/Ceramic_art" title="Ceramic art">Ceramic</a> / <a href="/wiki/Glass_art" title="Glass art">glass design</a></li> <li><a href="/wiki/Fashion_design" title="Fashion design">Fashion design</a> <ul><li><a href="/wiki/Costume_design" title="Costume design">Costume design</a></li> <li><a href="/wiki/Jewellery_design" title="Jewellery design">Jewellery design</a></li></ul></li> <li><a href="/wiki/Floral_design" title="Floral design">Floral design</a></li> <li><a href="/wiki/Game_art_design" title="Game art design">Game art design</a></li> <li><a href="/wiki/Property_designer" class="mw-redirect" title="Property designer">Property design</a></li> <li><a href="/wiki/Scenic_design" title="Scenic design">Scenic design</a></li> <li><a href="/wiki/Sound_design" title="Sound design">Sound design</a></li> <li><a href="/wiki/Lighting_design" title="Lighting design">Stage/set lighting design</a></li> <li><a href="/wiki/Textile_design" title="Textile design">Textile design</a></li></ul> </div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%">Other<br />design<br />& <a href="/wiki/Engineering" title="Engineering">engineering</a></th><td class="navbox-list-with-group navbox-list navbox-even" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Algorithm_design" class="mw-redirect" title="Algorithm design">Algorithm design</a></li> <li><a href="/wiki/Behavioural_design" title="Behavioural design">Behavioural design</a></li> <li><a href="/wiki/Boiler_design" title="Boiler design">Boiler design</a></li> <li><a href="/wiki/Database_design" title="Database design">Database design</a></li> <li><a href="/wiki/Drug_design" title="Drug design">Drug design</a></li> <li><a href="/wiki/Electrical_system_design" title="Electrical system design">Electrical system design</a></li> <li><a href="/wiki/Design_of_experiments" title="Design of experiments">Experimental design</a></li> <li><a href="/wiki/Filter_design" title="Filter design">Filter design</a></li> <li><a href="/wiki/Geometric_design" title="Geometric design">Geometric design</a></li> <li><a href="/wiki/Work_design" title="Work design">Work design</a></li> <li><a href="/wiki/Integrated_circuit_design" title="Integrated circuit design">Integrated circuit design</a> <ul><li><a href="/wiki/Circuit_design" title="Circuit design">Circuit design</a></li> <li><a href="/wiki/Physical_design_(electronics)" title="Physical design (electronics)">Physical design</a></li> <li><a href="/wiki/Power_network_design_(IC)" title="Power network design (IC)">Power network design</a></li></ul></li> <li><a href="/wiki/Mechanism_design" title="Mechanism design">Mechanism design</a></li> <li><a href="/wiki/Nuclear_weapon_design" title="Nuclear weapon design">Nuclear weapon design</a></li> <li><a href="/wiki/Nucleic_acid_design" title="Nucleic acid design">Nucleic acid design</a></li> <li><a href="/wiki/Organizational_architecture" title="Organizational architecture">Organization design</a></li> <li><a href="/wiki/Process_design" title="Process design">Process design</a></li> <li><a href="/wiki/Processor_design" title="Processor design">Processor design</a></li> <li><a class="mw-selflink selflink">Protein design</a></li> <li><a href="/wiki/Research_design" title="Research design">Research design</a></li> <li><a href="/wiki/Social_design" title="Social design">Social design</a></li> <li><a href="/wiki/Software_design" title="Software design">Software design</a></li> <li><a href="/wiki/Spacecraft_design" title="Spacecraft design">Spacecraft design</a></li> <li><a href="/wiki/Strategic_design" title="Strategic design">Strategic design</a></li> <li><a href="/wiki/Systems_design" title="Systems design">Systems design</a></li></ul> </div></td></tr></tbody></table><div></div></td></tr></tbody></table><div></div></td></tr><tr><td colspan="2" class="navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em"></div><table class="nowraplinks mw-collapsible mw-collapsed navbox-subgroup" style="border-spacing:0"><tbody><tr><th scope="col" class="navbox-title" colspan="2"><div id="Approaches931" style="font-size:114%;margin:0 4em">Approaches</div></th></tr><tr><td colspan="2" class="navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Activity-centered_design" title="Activity-centered design">Activity-centered</a></li> <li><a href="/wiki/Adaptive_web_design" title="Adaptive web design">Adaptive web</a></li> <li><a href="/wiki/Affective_design" title="Affective design">Affective</a></li> <li><a href="/wiki/Brainstorming" title="Brainstorming">Brainstorming</a></li> <li><a href="/wiki/Design_by_committee" title="Design by committee">By committee</a></li> <li><a href="/wiki/Design_by_contract" title="Design by contract">By contract</a></li> <li><a href="/wiki/C-K_theory" title="C-K theory">C-K theory</a></li> <li><a href="/wiki/Design_closure" title="Design closure">Closure</a></li> <li><a href="/wiki/Participatory_design" title="Participatory design">Co-design</a></li> <li><a href="/w/index.php?title=Concept-oriented_design&action=edit&redlink=1" class="new" title="Concept-oriented design (page does not exist)">Concept-oriented</a></li> <li><a href="/wiki/Configuration_design" title="Configuration design">Configuration</a></li> <li><a href="/wiki/Contextual_design" title="Contextual design">Contextual</a></li> <li><a href="/wiki/Continuous_design" title="Continuous design">Continuous</a></li> <li><a href="/wiki/Cradle-to-cradle_design" title="Cradle-to-cradle design">Cradle-to-cradle</a></li> <li><a href="/wiki/Creative_problem-solving" title="Creative problem-solving">Creative problem-solving</a></li> <li><a href="/wiki/Creativity_techniques" title="Creativity techniques">Creativity techniques</a></li> <li><a href="/wiki/Critical_design" title="Critical design">Critical</a> <ul><li><a href="/wiki/Design_fiction" title="Design fiction">Design fiction</a></li></ul></li> <li><a href="/wiki/Defensive_design" title="Defensive design">Defensive</a></li> <li><a href="/wiki/Design%E2%80%93bid%E2%80%93build" title="Design–bid–build">Design–bid–build</a></li> <li><a href="/wiki/Design%E2%80%93build" title="Design–build">Design–build</a> <ul><li><a href="/wiki/Architect-led_design%E2%80%93build" class="mw-redirect" title="Architect-led design–build">architect-led</a></li></ul></li> <li><a href="/wiki/Diffuse_design" title="Diffuse design">Diffuse</a></li> <li><a href="/wiki/Domain-driven_design" title="Domain-driven design">Domain-driven</a></li> <li><a href="/wiki/Ecological_design" title="Ecological design">Ecological design</a></li> <li><a href="/wiki/Energy_neutral_design" title="Energy neutral design">Energy neutral</a></li> <li><a href="/wiki/Engineering_design_process" title="Engineering design process">Engineering design process</a> <ul><li><a href="/wiki/Probabilistic_design" title="Probabilistic design">Probabilistic design</a></li></ul></li> <li><a href="/wiki/Error-tolerant_design" title="Error-tolerant design">Error-tolerant</a></li> <li><a href="/wiki/Fault-tolerant_design" class="mw-redirect" title="Fault-tolerant design">Fault-tolerant</a></li> <li><a href="/wiki/Framework-oriented_design" title="Framework-oriented design">Framework-oriented</a></li> <li><a href="/wiki/Design_for_assembly" title="Design for assembly">For assembly</a></li> <li><a href="/wiki/Behavioural_design" title="Behavioural design">For behaviour change</a></li> <li><a href="/wiki/Design_for_manufacturability" title="Design for manufacturability">For manufacturability</a></li> <li><a href="/wiki/Design_for_Six_Sigma" title="Design for Six Sigma">For Six Sigma</a></li> <li><a href="/wiki/Design_for_testing" title="Design for testing">For testing</a></li> <li><a href="/wiki/Design_for_X" title="Design for X">For X</a></li> <li><a href="/wiki/Functional_design" title="Functional design">Functional</a></li> <li><a href="/wiki/Generative_design" title="Generative design">Generative</a></li> <li><a href="/wiki/Geodesign" title="Geodesign">Geodesign</a></li> <li><a href="/wiki/Human-centered_design" title="Human-centered design">HCD</a></li> <li><a href="/wiki/High-level_design" title="High-level design">High-level</a></li> <li><a href="/wiki/Inclusive_design" title="Inclusive design">Inclusive</a></li> <li><a href="/wiki/Integrated_design" title="Integrated design">Integrated</a></li> <li><a href="/wiki/Integrated_topside_design" title="Integrated topside design">Integrated topside</a></li> <li><a href="/wiki/Intelligence-based_design" title="Intelligence-based design">Intelligence-based</a></li> <li><a href="/wiki/Iterative_design" title="Iterative design">Iterative</a></li> <li><a href="/wiki/KISS_principle" title="KISS principle">KISS principle</a></li> <li><a href="/wiki/Low-level_design" title="Low-level design">Low-level</a></li> <li><a href="/wiki/Metadesign" title="Metadesign">Metadesign</a></li> <li><a href="/wiki/Mind_map" title="Mind map">Mind mapping</a></li> <li><a href="/wiki/Modular_design" title="Modular design">Modular</a></li> <li><a href="/wiki/New_Wave_(design)" title="New Wave (design)">New Wave</a></li> <li><a href="/wiki/Object-oriented_design" class="mw-redirect" title="Object-oriented design">Object-oriented</a></li> <li><a href="/wiki/Open-design_movement" title="Open-design movement">Open</a></li> <li><a href="/wiki/Parametric_design" title="Parametric design">Parametric</a></li> <li><a href="/wiki/Participatory_design" title="Participatory design">Participatory</a></li> <li><a href="/wiki/Platform-based_design" title="Platform-based design">Platform-based</a></li> <li><a href="/wiki/Policy-based_design" class="mw-redirect" title="Policy-based design">Policy-based</a></li> <li><a href="/wiki/Process-centered_design" title="Process-centered design">Process-centered</a></li> <li><a href="/wiki/Public_interest_design" title="Public interest design">Public interest</a></li> <li><a href="/wiki/Rational_design" title="Rational design">Rational</a></li> <li><a href="/wiki/Regenerative_design" title="Regenerative design">Regenerative</a></li> <li><a href="/wiki/Reliability_engineering" title="Reliability engineering">Reliability engineering</a></li> <li><a href="/wiki/Research-based_design" title="Research-based design">Research-based</a></li> <li><a href="/wiki/Responsibility-driven_design" title="Responsibility-driven design">Responsibility-driven</a></li> <li><a href="/wiki/Responsive_web_design" title="Responsive web design">RWD</a></li> <li><a href="/wiki/Safe-life_design" title="Safe-life design">Safe-life</a></li> <li><a href="/wiki/Sustainable_design" title="Sustainable design">Sustainable</a></li> <li><a href="/wiki/Systemic_design" title="Systemic design">Systemic</a> <ul><li><a href="/wiki/Systems-oriented_design" title="Systems-oriented design">SOD</a></li></ul></li> <li><a href="/wiki/Tableless_web_design" title="Tableless web design">Tableless web</a></li> <li><a href="/wiki/Theory_of_constraints" title="Theory of constraints">Theory of constraints</a></li> <li><a href="/wiki/Top-down_and_bottom-up_design" class="mw-redirect" title="Top-down and bottom-up design">Top-down and bottom-up</a></li> <li><a href="/wiki/Transformation_design" title="Transformation design">Transformation</a></li> <li><a href="/wiki/Transgenerational_design" title="Transgenerational design">Transgenerational</a></li> <li><a href="/wiki/TRIZ" title="TRIZ">TRIZ</a></li> <li><a href="/wiki/Universal_design" title="Universal design">Universal</a> <ul><li><a href="/wiki/Design_for_All_(in_ICT)" title="Design for All (in ICT)">Design for All</a></li></ul></li> <li><a href="/wiki/Usage-centered_design" title="Usage-centered design">Usage-centered</a></li> <li><a href="/wiki/Use-centered_design" title="Use-centered design">Use-centered</a></li> <li><a href="/wiki/User-centered_design" title="User-centered design">User-centered</a> <ul><li><a href="/wiki/Empathic_design" title="Empathic design">Empathic</a></li></ul></li> <li><a href="/wiki/User_innovation" title="User innovation">User innovation</a></li> <li><a href="/wiki/Value-driven_design" title="Value-driven design">Value-driven</a></li> <li><a href="/wiki/Value_sensitive_design" title="Value sensitive design">Value sensitive</a> <ul><li><a href="/wiki/Privacy_by_design" title="Privacy by design">Privacy by</a></li></ul></li></ul> <ul><li>Design <a href="/wiki/Design_choice" title="Design choice">choice</a></li> <li><a href="/wiki/Design_computing" title="Design computing">computing</a></li> <li><a href="/wiki/Design_controls" title="Design controls">controls</a></li> <li><a href="/wiki/Design_culture" title="Design culture">culture</a></li> <li><a href="/wiki/Design_flow_(EDA)" title="Design flow (EDA)">flow</a></li> <li><a href="/wiki/Design_leadership" title="Design leadership">leadership</a></li> <li><a href="/wiki/Design_management" title="Design management">management</a></li> <li><a href="/wiki/Design_marker" title="Design marker">marker</a></li> <li><a href="/wiki/Design_methods" title="Design methods">methods</a></li> <li><a href="/wiki/Design_pattern" title="Design pattern">pattern</a></li> <li><a href="/wiki/Design_research" title="Design research">research</a></li> <li><a href="/wiki/Design_science" title="Design science">science</a></li> <li><a href="/wiki/Design_sprint" title="Design sprint">sprint</a></li> <li><a href="/wiki/Design_strategy" class="mw-redirect" title="Design strategy">strategy</a></li> <li><a href="/wiki/Design_theory" title="Design theory">theory</a></li> <li><a href="/wiki/Design_thinking" title="Design thinking">thinking</a></li></ul> </div></td></tr></tbody></table><div></div></td></tr><tr><td colspan="2" class="navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em"></div><table class="nowraplinks mw-collapsible mw-collapsed navbox-subgroup" style="border-spacing:0"><tbody><tr><th scope="col" class="navbox-title" colspan="2"><div id="ToolsIntellectual_propertyOrganizationsAwards931" style="font-size:114%;margin:0 4em"><div class="hlist"><ul><li>Tools</li><li>Intellectual property</li><li>Organizations</li><li>Awards</li></ul></div></div></th></tr><tr><td colspan="2" class="navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em"></div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th scope="row" class="navbox-group" style="width:1%"><a href="/wiki/Design_tool" title="Design tool">Tools</a></th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Algorithms-Aided_Design" title="Algorithms-Aided Design">AAD</a></li> <li><a href="/wiki/Architectural_model" title="Architectural model">Architectural model</a></li> <li><a href="/wiki/Blueprint" title="Blueprint">Blueprint</a></li> <li><a href="/wiki/Comprehensive_layout" title="Comprehensive layout">Comprehensive layout</a></li> <li><a href="/wiki/Computer-aided_design" title="Computer-aided design">CAD</a> <ul><li><a href="/wiki/Computer-aided_industrial_design" title="Computer-aided industrial design">CAID</a></li> <li><a href="/wiki/Virtual_home_design_software" title="Virtual home design software">Virtual home design software</a></li></ul></li> <li><a href="/wiki/Computer-automated_design" title="Computer-automated design">CAutoD</a></li> <li><a href="/wiki/Design_quality_indicator" title="Design quality indicator">Design quality indicator</a></li> <li><a href="/wiki/Electronic_design_automation" title="Electronic design automation">Electronic design automation</a></li> <li><a href="/wiki/Flowchart" title="Flowchart">Flowchart</a></li> <li><a href="/wiki/Mockup" title="Mockup">Mockup</a></li> <li><a href="/wiki/Design_specification" title="Design specification">Design specification</a></li> <li><a href="/wiki/Prototype" title="Prototype">Prototype</a></li> <li><a href="/wiki/Sketch_(drawing)" title="Sketch (drawing)">Sketch</a></li> <li><a href="/wiki/Storyboard" title="Storyboard">Storyboard</a></li> <li><a href="/wiki/Technical_drawing" title="Technical drawing">Technical drawing</a></li> <li><a href="/wiki/HTML_editor" title="HTML editor">HTML editor</a></li> <li><a href="/wiki/Website_wireframe" title="Website wireframe">Website wireframe</a></li></ul> </div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%">Intellectual<br />property</th><td class="navbox-list-with-group navbox-list navbox-even" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Community_design" title="Community design">Community design</a></li> <li><a href="/wiki/Design_around" title="Design around">Design around</a></li> <li><a href="/wiki/Design_infringement" title="Design infringement">Design infringement</a></li> <li><a href="/wiki/Design_patent" title="Design patent">Design patent</a></li> <li><a href="/wiki/Fashion_design_copyright" title="Fashion design copyright">Fashion design copyright</a></li> <li><i><a href="/wiki/Geschmacksmuster" title="Geschmacksmuster">Geschmacksmuster</a></i></li> <li><a href="/wiki/Industrial_design_right" title="Industrial design right">Industrial design rights</a> <ul><li><a href="/wiki/Industrial_design_rights_in_the_European_Union" title="Industrial design rights in the European Union">European Union</a></li></ul></li></ul> </div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%">Organizations</th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/American_Institute_of_Graphic_Arts" title="American Institute of Graphic Arts">American Institute of Graphic Arts</a></li> <li><a href="/wiki/Chartered_Society_of_Designers" title="Chartered Society of Designers">Chartered Society of Designers</a></li> <li><a href="/wiki/Design_and_Industries_Association" title="Design and Industries Association">Design and Industries Association</a></li> <li><a href="/wiki/Design_Council" title="Design Council">Design Council</a></li> <li><a href="/wiki/International_Forum_Design" title="International Forum Design">International Forum Design</a></li> <li><a href="/wiki/Design_Research_Society" title="Design Research Society">Design Research Society</a></li></ul> </div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%">Awards</th><td class="navbox-list-with-group navbox-list navbox-even" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/European_Design_Award" class="mw-redirect" title="European Design Award">European Design Award</a></li> <li><a href="/wiki/German_Design_Award" title="German Design Award">German Design Award</a></li> <li><a href="/wiki/Good_Design_Award_(Museum_of_Modern_Art)" title="Good Design Award (Museum of Modern Art)">Good Design Award (Museum of Modern Art)</a></li> <li><a href="/wiki/Good_Design_Award_(Chicago_Athenaeum)" class="mw-redirect" title="Good Design Award (Chicago Athenaeum)">Good Design Award (Chicago Athenaeum)</a></li> <li><a href="/wiki/Graphex" class="mw-redirect" title="Graphex">Graphex</a></li> <li><a href="/wiki/IF_Product_Design_Award" title="IF Product Design Award">IF Product Design Award</a></li> <li><a href="/wiki/James_Dyson_Award" title="James Dyson Award">James Dyson Award</a></li> <li><a href="/wiki/Prince_Philip_Designers_Prize" title="Prince Philip Designers Prize">Prince Philip Designers Prize</a></li></ul> </div></td></tr></tbody></table><div></div></td></tr></tbody></table><div></div></td></tr><tr><td colspan="2" class="navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em"></div><table class="nowraplinks mw-collapsible mw-collapsed navbox-subgroup" style="border-spacing:0"><tbody><tr><th scope="col" class="navbox-title" colspan="2"><div id="Related_topics931" style="font-size:114%;margin:0 4em">Related topics</div></th></tr><tr><td colspan="2" class="navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Agile_software_development" title="Agile software development">Agile</a></li> <li><a href="/wiki/Concept_art" title="Concept art">Concept art</a></li> <li><a href="/wiki/Conceptual_design" title="Conceptual design">Conceptual design</a></li> <li><a href="/wiki/Creative_industries" title="Creative industries">Creative industries</a></li> <li><a href="/wiki/Cultural_icon" title="Cultural icon">Cultural icon</a></li> <li><a href="/wiki/.design" title=".design">.design</a></li> <li><a href="/wiki/Enterprise_architecture" title="Enterprise architecture">Enterprise architecture</a></li> <li><a href="/wiki/Form_factor_(design)" title="Form factor (design)">Form factor</a></li> <li><a href="/wiki/Futures_studies" title="Futures studies">Futures studies</a></li> <li><a href="/wiki/Indie_design" title="Indie design">Indie design</a></li> <li><a href="/wiki/Innovation_management" title="Innovation management">Innovation management</a></li> <li><a href="/wiki/Intelligent_design" title="Intelligent design">Intelligent design</a></li> <li><a href="/wiki/Lean_startup" title="Lean startup">Lean startup</a></li> <li><a href="/wiki/New_product_development" title="New product development">New product development</a></li> <li><a href="/wiki/OODA_loop" title="OODA loop">OODA loop</a></li> <li><a href="/wiki/Philosophy_of_design" title="Philosophy of design">Philosophy of design</a></li> <li><a href="/wiki/Process_simulation" title="Process simulation">Process simulation</a></li> <li><a href="/wiki/Slow_design" class="mw-redirect" title="Slow design">Slow design</a></li> <li><a href="/wiki/STEAM_fields" class="mw-redirect" title="STEAM fields">STEAM fields</a></li> <li><a href="/wiki/Argument_from_poor_design" title="Argument from poor design">Unintelligent design</a></li> <li><a href="/wiki/Visualization_(graphics)" title="Visualization (graphics)">Visualization</a></li> <li><a href="/wiki/Wicked_problem" title="Wicked problem">Wicked problem</a></li></ul> <ul><li>Design <a href="/wiki/Design_brief" title="Design brief">brief</a></li> <li><a href="/wiki/Design_change" title="Design change">change</a></li> <li><a href="/wiki/Design_classic" title="Design classic">classic</a></li> <li><a href="/wiki/Design_competition" title="Design competition">competition</a> <ul><li><a href="/wiki/Architectural_design_competition" title="Architectural design competition">architectural</a></li> <li><a href="/wiki/Student_design_competition" title="Student design competition">student</a></li></ul></li> <li><a href="/wiki/Design_director" title="Design director">director</a></li> <li><a href="/wiki/Design_education" title="Design education">education</a></li> <li><a href="/wiki/Design_elements" title="Design elements">elements</a></li> <li><a href="/wiki/Design_engineer" title="Design engineer">engineer</a></li> <li><a href="/wiki/Design_firm" class="mw-redirect" title="Design firm">firm</a></li> <li><a href="/wiki/Design_history" title="Design history">history</a></li> <li><a href="/wiki/Design_knowledge" title="Design knowledge">knowledge</a></li> <li><a href="/wiki/Design_language" title="Design language">language</a></li> <li><a href="/wiki/Design_life" title="Design life">life</a></li> <li><a href="/wiki/Design_load" title="Design load">load</a></li> <li><a href="/wiki/Design_museum" title="Design museum">museum</a></li> <li><a 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