%!PS-Adobe-2.0 %%Creator: dvips(k) 2023.1 (TeX Live 2023) Copyright 2023 Radical Eye Software %%Title: arXiv:2503.13522v3 [q-bio.BM] 29 Mar 2025 %%CreationDate: Tue Apr 1 01:58:38 2025 %%Pages: 192 %%PageOrder: Ascend %%BoundingBox: 0 0 612 792 %%DocumentFonts: Roboto-Regular Roboto-Italic Roboto-Bold %%DocumentPaperSizes: Letter %%EndComments %%BeginDefaults %%ViewingOrientation: 1 0 0 1 %%EndDefaults %DVIPSWebPage: (www.radicaleye.com) %DVIPSCommandLine: dvips -R2 -P pk -z main.dvi -o %DVIPSParameters: dpi=600 %DVIPSSource: TeX output 2025.04.01:0158 %%BeginProcSet: tex.pro 0 0 %! /TeXDict 300 dict def TeXDict begin/N{def}def/B{bind def}N/S{exch}N/X{S N}B/A{dup}B/TR{translate}N/isls false N/vsize 11 72 mul N/hsize 8.5 72 mul N/landplus90{false}def/@rigin{isls{[0 landplus90{1 -1}{-1 1}ifelse 0 0 0]concat}if 72 Resolution div 72 VResolution div neg scale isls{ landplus90{VResolution 72 div vsize mul 0 exch}{Resolution -72 div hsize mul 0}ifelse TR}if Resolution VResolution vsize -72 div 1 add mul TR[ matrix currentmatrix{A A round sub abs 0.00001 lt{round}if}forall round exch round exch]setmatrix}N/@landscape{/isls true N}B/@manualfeed{ statusdict/manualfeed true put}B/@copies{/#copies X}B/FMat[1 0 0 -1 0 0] N/FBB[0 0 0 0]N/nn 0 N/IEn 0 N/ctr 0 N/df-tail{/nn 8 dict N nn begin /FontType 3 N/FontMatrix fntrx N/FontBBox FBB N string/base X array /BitMaps X/BuildChar{CharBuilder}N/Encoding IEn N end A{/foo setfont}2 array copy cvx N load 0 nn put/ctr 0 N[}B/sf 0 N/df{/sf 1 N/fntrx FMat N df-tail}B/dfs{div/sf X/fntrx[sf 0 0 sf neg 0 0]N df-tail}B/E{pop nn A definefont setfont}B/Cw{Cd A length 5 sub get}B/Ch{Cd A length 4 sub get }B/Cx{128 Cd A length 3 sub get sub}B/Cy{Cd A length 2 sub get 127 sub} B/Cdx{Cd A length 1 sub get}B/Ci{Cd A type/stringtype ne{ctr get/ctr ctr 1 add N}if}B/CharBuilder{save 3 1 roll S A/base get 2 index get S /BitMaps get S get/Cd X pop/ctr 0 N Cdx 0 Cx Cy Ch sub Cx Cw add Cy setcachedevice Cw Ch true[1 0 0 -1 -.1 Cx sub Cy .1 sub]{Ci}imagemask restore}B/D{/cc X A type/stringtype ne{]}if nn/base get cc ctr put nn /BitMaps get S ctr S sf 1 ne{A A length 1 sub A 2 index S get sf div put }if put/ctr ctr 1 add N}B/I{cc 1 add D}B/bop{userdict/bop-hook known{ bop-hook}if/SI save N @rigin 0 0 moveto/V matrix currentmatrix A 1 get A mul exch 0 get A mul add .99 lt{/QV}{/RV}ifelse load def pop pop}N/eop{ SI restore userdict/eop-hook known{eop-hook}if showpage}N/@start{ userdict/start-hook known{start-hook}if pop/VResolution X/Resolution X 1000 div/DVImag X/IEn 256 array N 2 string 0 1 255{IEn S A 360 add 36 4 index cvrs cvn put}for pop 65781.76 div/vsize X 65781.76 div/hsize X}N /dir 0 def/dyy{/dir 0 def}B/dyt{/dir 1 def}B/dty{/dir 2 def}B/dtt{/dir 3 def}B/p{dir 2 eq{-90 rotate show 90 rotate}{dir 3 eq{-90 rotate show 90 rotate}{show}ifelse}ifelse}N/RMat[1 0 0 -1 0 0]N/BDot 260 string N/Rx 0 N/Ry 0 N/V{}B/RV/v{/Ry X/Rx X V}B statusdict begin/product where{pop false[(Display)(NeXT)(LaserWriter 16/600)]{A length product length le{A length product exch 0 exch getinterval eq{pop true exit}if}{pop}ifelse} forall}{false}ifelse end{{gsave TR -.1 .1 TR 1 1 scale Rx Ry false RMat{ BDot}imagemask grestore}}{{gsave TR -.1 .1 TR Rx Ry scale 1 1 false RMat {BDot}imagemask grestore}}ifelse B/QV{gsave newpath transform round exch round exch itransform moveto Rx 0 rlineto 0 Ry neg rlineto Rx neg 0 rlineto fill grestore}B/a{moveto}B/delta 0 N/tail{A/delta X 0 rmoveto}B /M{S p delta add tail}B/b{S p tail}B/c{-4 M}B/d{-3 M}B/e{-2 M}B/f{-1 M} B/g{0 M}B/h{1 M}B/i{2 M}B/j{3 M}B/k{4 M}B/w{0 rmoveto}B/l{p -4 w}B/m{p -3 w}B/n{p -2 w}B/o{p -1 w}B/q{p 1 w}B/r{p 2 w}B/s{p 3 w}B/t{p 4 w}B/x{ 0 S rmoveto}B/y{3 2 roll p a}B/bos{/SS save N}B/eos{SS restore}B end %%EndProcSet %%BeginProcSet: l3backend-dvips.pro 0 0 %% %% This is file `l3backend-dvips.pro', %% generated with the docstrip utility. %% %% The original source files were: %% %% l3backend-header.dtx (with options: `header,dvips') %% %% Copyright (C) 2019-2023 The LaTeX Project %% %% It may be distributed and/or modified under the conditions of %% the LaTeX Project Public License (LPPL), either version 1.3c of %% this license or (at your option) any later version. 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/aacute /acircumflex /atilde /adieresis /aring /ae /ccedilla /egrave /eacute /ecircumflex /edieresis /igrave /iacute /icircumflex /idieresis %F0 /eth /ntilde /ograve /oacute /ocircumflex /otilde /odieresis /oe /oslash /ugrave /uacute /ucircumflex /udieresis /yacute /thorn /germandbls ] def % Command line: 'otftotfm --automatic --encoding=fontools_t1 % --tfm-directory=texmf/fonts/tfm/google/roboto % --vf-directory=texmf/fonts/vf/google/roboto % --type1-directory=texmf/fonts/type1/google/roboto % --truetype-directory=texmf/fonts/truetype/google/roboto % --encoding-directory=texmf/fonts/enc/dvips/roboto % --map-file=texmf/fonts/map/dvips/roboto/Roboto.map --no-updmap % --coding-scheme=EXTENDED TEX FONT ENCODING - LATIN --feature=kern % --feature=liga --feature=lnum --feature=pnum --ligkern=f i =: fi % --ligkern=f l =: fl --ligkern=f f =: ff --ligkern=ff i =: ffi --ligkern=ff % l =: ffl --x-height=x Roboto-BlackItalic.otf Roboto-BlackItalic-lf-t1' %%EndProcSet %%BeginProcSet: 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TeXDict begin/SDict 200 dict N SDict begin/@SpecialDefaults{/hs 612 N /vs 792 N/ho 0 N/vo 0 N/hsc 1 N/vsc 1 N/ang 0 N/CLIP 0 N/rwiSeen false N /rhiSeen false N/letter{}N/note{}N/a4{}N/legal{}N}B/@scaleunit 100 N /@hscale{@scaleunit div/hsc X}B/@vscale{@scaleunit div/vsc X}B/@hsize{ /hs X/CLIP 1 N}B/@vsize{/vs X/CLIP 1 N}B/@clip{/CLIP 2 N}B/@hoffset{/ho X}B/@voffset{/vo X}B/@angle{/ang X}B/@rwi{10 div/rwi X/rwiSeen true N}B /@rhi{10 div/rhi X/rhiSeen true N}B/@llx{/llx X}B/@lly{/lly X}B/@urx{ /urx X}B/@ury{/ury X}B/magscale true def end/@MacSetUp{userdict/md known {userdict/md get type/dicttype eq{userdict begin md length 10 add md maxlength ge{/md md dup length 20 add dict copy def}if end md begin /letter{}N/note{}N/legal{}N/od{txpose 1 0 mtx defaultmatrix dtransform S atan/pa X newpath clippath mark{transform{itransform moveto}}{transform{ itransform lineto}}{6 -2 roll transform 6 -2 roll transform 6 -2 roll transform{itransform 6 2 roll itransform 6 2 roll itransform 6 2 roll curveto}}{{closepath}}pathforall newpath counttomark array astore/gc xdf pop ct 39 0 put 10 fz 0 fs 2 F/|______Courier fnt invertflag{PaintBlack} if}N/txpose{pxs pys scale ppr aload pop por{noflips{pop S neg S TR pop 1 -1 scale}if xflip yflip and{pop S neg S TR 180 rotate 1 -1 scale ppr 3 get ppr 1 get neg sub neg ppr 2 get ppr 0 get neg sub neg TR}if xflip yflip not and{pop S neg S TR pop 180 rotate ppr 3 get ppr 1 get neg sub neg 0 TR}if yflip xflip not and{ppr 1 get neg ppr 0 get neg TR}if}{ noflips{TR pop pop 270 rotate 1 -1 scale}if xflip yflip and{TR pop pop 90 rotate 1 -1 scale ppr 3 get ppr 1 get neg sub neg ppr 2 get ppr 0 get neg sub neg TR}if xflip yflip not and{TR pop pop 90 rotate ppr 3 get ppr 1 get neg sub neg 0 TR}if yflip xflip not and{TR pop pop 270 rotate ppr 2 get ppr 0 get neg sub neg 0 S TR}if}ifelse scaleby96{ppr aload pop 4 -1 roll add 2 div 3 1 roll add 2 div 2 copy TR .96 dup scale neg S neg S TR}if}N/cp{pop pop showpage pm restore}N end}if}if}N/normalscale{ Resolution 72 div VResolution 72 div neg scale magscale{DVImag dup scale }if 0 setgray}N/@beginspecial{SDict begin/SpecialSave save N gsave normalscale currentpoint TR @SpecialDefaults count/ocount X/dcount countdictstack N}N/@setspecial{CLIP 1 eq{newpath 0 0 moveto hs 0 rlineto 0 vs rlineto hs neg 0 rlineto closepath clip}if ho vo TR hsc vsc scale ang rotate rwiSeen{rwi urx llx sub div rhiSeen{rhi ury lly sub div}{dup} ifelse scale llx neg lly neg TR}{rhiSeen{rhi ury lly sub div dup scale llx neg lly neg TR}if}ifelse CLIP 2 eq{newpath llx lly moveto urx lly lineto urx ury lineto llx ury lineto closepath clip}if/showpage{}N /erasepage{}N/setpagedevice{pop}N/copypage{}N newpath}N/@endspecial{ count ocount sub{pop}repeat countdictstack dcount sub{end}repeat grestore SpecialSave restore end}N/@defspecial{SDict begin}N /@fedspecial{end}B/li{lineto}B/rl{rlineto}B/rc{rcurveto}B/np{/SaveX currentpoint/SaveY X N 1 setlinecap newpath}N/st{stroke SaveX SaveY moveto}N/fil{fill SaveX SaveY moveto}N/ellipse{/endangle X/startangle X /yrad X/xrad X/savematrix matrix currentmatrix N TR xrad yrad scale 0 0 1 startangle endangle arc savematrix setmatrix}N end %%EndProcSet %%BeginProcSet: color.pro 0 0 %! 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0.89 0.94 0.28 setcmykcolor}DC/Red{ 0 1 1 0 setcmykcolor}DC/OrangeRed{0 1 0.50 0 setcmykcolor}DC/RubineRed{ 0 1 0.13 0 setcmykcolor}DC/WildStrawberry{0 0.96 0.39 0 setcmykcolor}DC /Salmon{0 0.53 0.38 0 setcmykcolor}DC/CarnationPink{0 0.63 0 0 setcmykcolor}DC/Magenta{0 1 0 0 setcmykcolor}DC/VioletRed{0 0.81 0 0 setcmykcolor}DC/Rhodamine{0 0.82 0 0 setcmykcolor}DC/Mulberry{0.34 0.90 0 0.02 setcmykcolor}DC/RedViolet{0.07 0.90 0 0.34 setcmykcolor}DC /Fuchsia{0.47 0.91 0 0.08 setcmykcolor}DC/Lavender{0 0.48 0 0 setcmykcolor}DC/Thistle{0.12 0.59 0 0 setcmykcolor}DC/Orchid{0.32 0.64 0 0 setcmykcolor}DC/DarkOrchid{0.40 0.80 0.20 0 setcmykcolor}DC/Purple{ 0.45 0.86 0 0 setcmykcolor}DC/Plum{0.50 1 0 0 setcmykcolor}DC/Violet{ 0.79 0.88 0 0 setcmykcolor}DC/RoyalPurple{0.75 0.90 0 0 setcmykcolor}DC /BlueViolet{0.86 0.91 0 0.04 setcmykcolor}DC/Periwinkle{0.57 0.55 0 0 setcmykcolor}DC/CadetBlue{0.62 0.57 0.23 0 setcmykcolor}DC /CornflowerBlue{0.65 0.13 0 0 setcmykcolor}DC/MidnightBlue{0.98 0.13 0 0.43 setcmykcolor}DC/NavyBlue{0.94 0.54 0 0 setcmykcolor}DC/RoyalBlue{1 0.50 0 0 setcmykcolor}DC/Blue{1 1 0 0 setcmykcolor}DC/Cerulean{0.94 0.11 0 0 setcmykcolor}DC/Cyan{1 0 0 0 setcmykcolor}DC/ProcessBlue{0.96 0 0 0 setcmykcolor}DC/SkyBlue{0.62 0 0.12 0 setcmykcolor}DC/Turquoise{0.85 0 0.20 0 setcmykcolor}DC/TealBlue{0.86 0 0.34 0.02 setcmykcolor}DC /Aquamarine{0.82 0 0.30 0 setcmykcolor}DC/BlueGreen{0.85 0 0.33 0 setcmykcolor}DC/Emerald{1 0 0.50 0 setcmykcolor}DC/JungleGreen{0.99 0 0.52 0 setcmykcolor}DC/SeaGreen{0.69 0 0.50 0 setcmykcolor}DC/Green{1 0 1 0 setcmykcolor}DC/ForestGreen{0.91 0 0.88 0.12 setcmykcolor}DC /PineGreen{0.92 0 0.59 0.25 setcmykcolor}DC/LimeGreen{0.50 0 1 0 setcmykcolor}DC/YellowGreen{0.44 0 0.74 0 setcmykcolor}DC/SpringGreen{ 0.26 0 0.76 0 setcmykcolor}DC/OliveGreen{0.64 0 0.95 0.40 setcmykcolor} DC/RawSienna{0 0.72 1 0.45 setcmykcolor}DC/Sepia{0 0.83 1 0.70 setcmykcolor}DC/Brown{0 0.81 1 0.60 setcmykcolor}DC/Tan{0.14 0.42 0.56 0 setcmykcolor}DC/Gray{0 0 0 0.50 setcmykcolor}DC/Black{0 0 0 1 setcmykcolor}DC/White{0 0 0 0 setcmykcolor}DC end %%EndProcSet %%BeginProcSet: hps.pro 0 0 %! /HPSdict 20 dict dup begin/braindeaddistill 50 def/rfch{dup length 1 sub 1 exch getinterval}bind def/splituri{dup(#)search{exch pop}{()exch} ifelse dup(file:)anchorsearch{pop exch pop 3 -1 roll pop false}{pop 3 -1 roll exch pop true}ifelse}bind def/lookuptarget{exch rfch dup /TargetAnchors where{pop TargetAnchors dup 3 -1 roll known{exch get true }{pop(target unknown:)print == false}ifelse}{pop pop (target dictionary unknown\012)print false}ifelse}bind def/savecount 0 def/stackstopped{count counttomark sub/savecount exch store stopped count savecount sub 1 sub dup 0 gt{{exch pop}repeat}{pop}ifelse}bind def /tempstring 128 string def/targetvalidate{1 index dup length 127 gt exch tempstring cvs dup(/)search{pop pop pop exch pop true exch}{pop}ifelse token{pop length 0 ne}{true}ifelse or not}bind def/targetdump-hook where {pop}{/targetdump-hook{dup mark exch gsave initmat setmatrix{{mark/Dest 4 2 roll targetvalidate{aload pop exch pop/Page 3 1 roll/View exch[exch /FitH exch]/DEST pdfmark}{cleartomark}ifelse}forall}stackstopped pop grestore}bind def}ifelse/baseurl{mark exch 1 dict dup 3 -1 roll/Base exch put/URI exch/DOCVIEW{pdfmark}stackstopped pop}bind def /externalhack systemdict/PDF known def/oldstyle true def/initmat matrix currentmatrix def/actiondict 2 dict dup/Subtype/URI put def /weblinkhandler{dup 3 1 roll mark 4 1 roll/Title 4 1 roll splituri 3 -1 roll dup length 0 gt{cvn/Dest exch 4 2 roll}{pop}ifelse{externalhack{ /HTTPFile exch}{actiondict dup 3 -1 roll/URI exch put/Action exch} ifelse}{externalhack{/HTTPFile exch}{/File exch/Action/GoToR}ifelse} ifelse counttomark 2 sub -1 roll aload pop/Rect 4 1 roll/Border 3 1 roll /Color exch oldstyle{/LNK}{/Subtype/Link/ANN}ifelse gsave initmat setmatrix{pdfmark}stackstopped grestore}bind def/externalhandler where{ pop}{/externalhandler{2 copy{weblinkhandler}exec{/externalhack externalhack not store 2 copy{weblinkhandler}exec{/externalhack externalhack not store/oldstyle false store 2 copy{weblinkhandler}exec{ (WARNING: external refs disabled\012)print/externalhandler{pop pop}bind store externalhandler}{pop pop}ifelse}{pop pop/externalhack externalhack not store}ifelse}{pop pop/externalhandler{weblinkhandler pop}bind store} ifelse}bind def}ifelse/pdfmnew{dup type/stringtype eq{externalhandler}{ exch dup rfch exch 3 -1 roll lookuptarget{mark 4 1 roll/Title 4 1 roll aload pop exch pop/Page 3 1 roll/View exch[exch/FitH exch]5 -1 roll aload pop/Rect 4 1 roll/Border 3 1 roll/Color exch/LNK gsave initmat setmatrix pdfmark grestore}{pop pop}ifelse}ifelse}bind def/pdfmold{dup type/stringtype eq{externalhandler}{exch dup rfch exch 3 -1 roll lookuptarget{mark 4 1 roll/Title 4 1 roll aload pop exch pop/Page 3 1 roll/View exch[exch/FitH exch]5 -1 roll aload pop pop 0 3 getinterval /Rect 3 1 roll/Border exch/LNK gsave initmat setmatrix pdfmark grestore} {pop pop}ifelse}ifelse}bind def/pdfm where{pop}{/pdfm /currentdistillerparams where{pop currentdistillerparams dup /CoreDistVersion known{/CoreDistVersion get}{0}ifelse dup braindeaddistill le{(WARNING: switching to old pdfm because version =) print ==/pdfmold}{pop/pdfmnew}ifelse load}{/pdfmark where{pop{dup type /stringtype eq{externalhandler}{2 copy mark 3 1 roll{pdfmnew} stackstopped{2 copy mark 3 1 roll{pdfmold}stackstopped{ (WARNING: pdfm disabled\012)print/pdfm{pop pop}store}{ (WARNING: new pdfm failed, switching to old pdfm\012)print/pdfm/pdfmold load store}ifelse}{/pdfm/pdfmnew load store}ifelse pop pop}ifelse}}{{ pop pop}}ifelse}ifelse bind def}ifelse end def %%EndProcSet TeXDict begin @defspecial systemdict /pdfmark known{userdict /?pdfmark systemdict /exec get put}{userdict /?pdfmark systemdict /pop get put userdict /pdfmark systemdict /cleartomark get put}ifelse /DvipsToPDF{72.27 mul Resolution div} def/PDFToDvips{72.27 div Resolution mul} def/BPToDvips{72 div Resolution mul}def product (Ghostscript) search {pop pop pop revision 927 gt}{pop false} ifelse{/BorderArrayPatch{} def}{/BorderArrayPatch{[exch{dup dup type/integertype eq exch type/realtype eq or{BPToDvips}if}forall]}def} ifelse /HyperBorder {1 PDFToDvips} def/H.V {pdf@hoff pdf@voff null} def/H.B {/Rect[pdf@llx pdf@lly pdf@urx pdf@ury]} def/H.S {currentpoint HyperBorder add /pdf@lly exch def dup DvipsToPDF 72 add /pdf@hoff exch def HyperBorder sub /pdf@llx exch def} def/H.L {2 sub dup/HyperBasePt exch def PDFToDvips /HyperBaseDvips exch def currentpoint HyperBaseDvips sub /pdf@ury exch def/pdf@urx exch def} def/H.A {H.L currentpoint exch pop vsize 72 sub exch DvipsToPDF HyperBasePt sub sub /pdf@voff exch def} def/H.R {currentpoint HyperBorder sub /pdf@ury exch def HyperBorder add /pdf@urx exch def currentpoint exch pop vsize 72 sub exch DvipsToPDF sub /pdf@voff exch def} def /pgfHrgb{/pgfheight exch def 0.75 setlinewidth [] 0 setdash /pgfshade {pgfArgb} def /pgfdir { dup 0 moveto dup 5 index lineto } bind def} bind def /pgfVrgb{/pgfheight exch def 0.75 setlinewidth [] 0 setdash /pgfshade {pgfArgb} def /pgfdir { dup 0 exch moveto dup 5 index exch lineto } bind def} bind def /pgfArgb{ /pgfdiff 8 index round cvi 8 index round cvi sub 2 mul 1 add def 2 index 6 index sub pgfdiff div 2 index 6 index sub pgfdiff div 2 index 6 index sub pgfdiff div pgfheight 9 index 9 index 9 index 14 index pgfdiff { 3 index 3 index 3 index setrgbcolor pgfdir stroke 4 -1 roll 7 index add 4 -1 roll 6 index add 4 -1 roll 5 index add 4 -1 roll .5 sub } repeat mark 15 1 roll cleartomark exch pop }bind def /pgfR1rgb{ newpath dup dup dup 0 360 arc clip newpath dup /pgfendx exch def /pgfendy exch def 0.875 setlinewidth [] 0 setdash /pgfshade {pgfRrgb} def /pgfstartx exch def /pgfstarty exch def /pgfdiffx pgfendx pgfstartx sub def /pgfdiffy pgfendy pgfstarty sub def dup /pgfdomb exch def }bind def /pgfR2rgb{ newpath 0.5 add pgfcircx pgfcircy 3 2 roll 0 360 arc setrgbcolor fill pop}bind def /pgfRrgb{ /pgfdiff 8 index round cvi 8 index round cvi sub 4 mul 1 add def /pgfcircx pgfstartx 9 index pgfdiffx pgfdomb div mul add def /pgfcircy pgfstarty 9 index pgfdiffy pgfdomb div mul add def /pgfcircxe pgfstartx 8 index pgfdiffx pgfdomb div mul add def /pgfcircye pgfstarty 8 index pgfdiffy pgfdomb div mul add def /pgfxstep pgfcircxe pgfcircx sub pgfdiff div def /pgfystep pgfcircye pgfcircy sub pgfdiff div def 2 index 6 index sub pgfdiff div 2 index 6 index sub pgfdiff div 2 index 6 index sub pgfdiff div 8 index 8 index 8 index 13 index pgfdiff { 3 index 3 index 3 index setrgbcolor pgfcircx pgfcircy 2 index 0 360 arc closepath stroke 4 -1 roll 6 index add 4 -1 roll 5 index add 4 -1 roll 4 index add 4 -1 roll .25 sub /pgfcircx pgfcircx pgfxstep add def /pgfcircy pgfcircy pgfystep add def } repeat mark 14 1 roll cleartomark exch pop }bind def /pgfHcmyk{ /pgfheight exch def 0.75 setlinewidth [] 0 setdash /pgfshade {pgfAcmyk} def /pgfdir { dup 0 moveto dup 6 index lineto } bind def} bind def /pgfVcmyk{ /pgfheight exch def 0.75 setlinewidth [] 0 setdash /pgfshade {pgfAcmyk} def /pgfdir { dup 0 exch moveto dup 6 index exch lineto } bind def} bind def /pgfAcmyk{ /pgfdiff 10 index round cvi 10 index round cvi sub 2 mul 1 add def 3 index 8 index sub pgfdiff div 3 index 8 index sub pgfdiff div 3 index 8 index sub pgfdiff div 3 index 8 index sub pgfdiff div pgfheight 12 index 12 index 12 index 12 index 18 index pgfdiff { 4 index 4 index 4 index 4 index setcmykcolor pgfdir stroke 5 -1 roll 9 index add 5 -1 roll 8 index add 5 -1 roll 7 index add 5 -1 roll 6 index add 5 -1 roll .5 sub } repeat mark 19 1 roll cleartomark exch pop }bind def /pgfR1cmyk{ newpath dup dup dup 0 360 arc clip newpath dup /pgfendx exch def /pgfendy exch def 0.875 setlinewidth [] 0 setdash /pgfshade {pgfRcmyk} def /pgfstartx exch def /pgfstarty exch def /pgfdiffx pgfendx pgfstartx sub def /pgfdiffy pgfendy pgfstarty sub def dup /pgfdomb exch def }bind def /pgfR2cmyk{ newpath 0.5 add pgfcircx pgfcircy 3 2 roll 0 360 arc setcmykcolor fill pop}bind def /pgfRcmyk{ /pgfdiff 10 index round cvi 10 index round cvi sub 4 mul 1 add def /pgfcircx pgfstartx 11 index pgfdiffx pgfdomb div mul add def /pgfcircy pgfstarty 11 index pgfdiffy pgfdomb div mul add def /pgfcircxe pgfstartx 10 index pgfdiffx pgfdomb div mul add def /pgfcircye pgfstarty 10 index pgfdiffy pgfdomb div mul add def /pgfxstep pgfcircxe pgfcircx sub pgfdiff div def /pgfystep pgfcircye pgfcircy sub pgfdiff div def 3 index 8 index sub pgfdiff div 3 index 8 index sub pgfdiff div 3 index 8 index sub pgfdiff div 3 index 8 index sub pgfdiff div 11 index 11 index 11 index 11 index 17 index pgfdiff { 4 index 4 index 4 index 4 index setcmykcolor pgfcircx pgfcircy 2 index 0 360 arc closepath stroke 5 -1 roll 8 index add 5 -1 roll 7 index add 5 -1 roll 6 index add 5 -1 roll 5 index add 5 -1 roll .25 sub /pgfcircx pgfcircx pgfxstep add def /pgfcircy pgfcircy pgfystep add def } repeat mark 18 1 roll cleartomark exch pop }bind def /pgfHgray{ /pgfheight exch def 0.75 setlinewidth [] 0 setdash /pgfshade {pgfAgray} def /pgfdir { dup 0 moveto dup 3 index lineto } bind def} bind def /pgfVgray{ /pgfheight exch def 0.75 setlinewidth [] 0 setdash /pgfshade {pgfAgray} def /pgfdir { dup 0 exch moveto dup 3 index exch lineto } bind def} bind def /pgfAgray{ /pgfdiff 4 index round cvi 4 index round cvi sub 2 mul 1 add def dup 2 index sub pgfdiff div pgfheight 3 index 6 index pgfdiff { 1 index setgray pgfdir stroke exch 3 index add exch .5 sub } repeat mark 7 1 roll cleartomark exch pop }bind def /pgfR1gray{ newpath dup dup dup 0 360 arc clip newpath dup /pgfendx exch def /pgfendy exch def 0.875 setlinewidth [] 0 setdash /pgfshade {pgfRgray} def /pgfstartx exch def /pgfstarty exch def /pgfdiffx pgfendx pgfstartx sub def /pgfdiffy pgfendy pgfstarty sub def dup /pgfdomb exch def }bind def /pgfR2gray{ newpath 0.5 add pgfcircx pgfcircy 3 2 roll 0 360 arc setgray fill pop}bind def /pgfRgray{ /pgfdiff 4 index round cvi 4 index round cvi sub 4 mul 1 add def /pgfcircx pgfstartx 5 index pgfdiffx pgfdomb div mul add def /pgfcircy pgfstarty 5 index pgfdiffy pgfdomb div mul add def /pgfcircxe pgfstartx 4 index pgfdiffx pgfdomb div mul add def /pgfcircye pgfstarty 4 index pgfdiffy pgfdomb div mul add def /pgfxstep pgfcircxe pgfcircx sub pgfdiff div def /pgfystep pgfcircye pgfcircy sub pgfdiff div def dup 2 index sub pgfdiff div 2 index 5 index pgfdiff { 1 index setgray pgfcircx pgfcircy 2 index 0 360 arc closepath stroke exch 2 index add exch .25 sub /pgfcircx pgfcircx pgfxstep add def /pgfcircy pgfcircy pgfystep add def } repeat mark 6 1 roll cleartomark exch pop }bind def /pgfsc{}bind def/pgffc{}bind def/pgfstr{stroke}bind def/pgffill{fill}bind def/pgfeofill{eofill}bind def/pgfe{a dup 0 rlineto exch 0 exch rlineto neg 0 rlineto closepath}bind def/pgfw{setlinewidth}bind def/pgfs{save pgfpd 72 Resolution div 72 VResolution div neg scale magscale{1 DVImag div dup scale}if pgfx neg pgfy neg translate pgffoa .setopacityalpha}bind def/pgfr{pgfsd restore}bind def userdict begin/pgfo{pgfsd /pgfx currentpoint /pgfy exch def def @beginspecial}bind def /pgfc{newpath @endspecial pgfpd}bind def /pgfsd{globaldict /pgfdelta /delta where {pop delta} {0} ifelse put}bind def/pgfpd{/delta globaldict /pgfdelta get def}bind def /.setblendmode where {pop} {/.setblendmode{pop}def} ifelse /.setfillconstantalpha where {pop /.setopacityalpha {.setfillconstantalpha} def} {/.setopacityalpha where {pop} {/.setopacityalpha {pop} def} ifelse} ifelse /.pgfsetfillopacityalpha{/pgffoa exch def /.setfillconstantalpha where {pop pgffoa .setfillconstantalpha} {/pgffill{gsave pgffoa .setopacityalpha fill 1 .setopacityalpha newpath fill grestore newpath}bind def /pgfeofill{gsave pgffoa .setopacityalpha eofill 1 .setopacityalpha newpath eofill grestore newpath}bind def} ifelse} bind def /.pgfsetstrokeopacityalpha{/pgfsoa exch def /.setstrokeconstantalpha where {pop pgfsoa .setstrokeconstantalpha} {/pgfstr{gsave pgfsoa .setopacityalpha stroke grestore newpath}bind def} ifelse}bind def /pgffoa 1 def /pgfsoa 1 def /.pushpdf14devicefilter where {pop [userdict /bop-hook known {userdict /bop-hook get aload pop} if {0 .pushpdf14devicefilter} aload pop] cvx userdict exch /bop-hook exch put [userdict /eop-hook known {userdict /eop-hook get aload pop} if {.poppdf14devicefilter} aload pop] cvx userdict exch /eop-hook exch put} if systemdict /pdfmark known not {userdict /pdfmark systemdict /cleartomark get put} if end /pgfwritesamplecmyk { 4 index 0 5 index pgfcheckcolorrange 255 mul round cvi put 4 index 1 4 index pgfcheckcolorrange 255 mul round cvi put 4 index 2 3 index pgfcheckcolorrange 255 mul round cvi put 4 index 3 2 index pgfcheckcolorrange 255 mul round cvi put pop pop pop pop } bind def /pgfwritesamplergb { 3 index 0 4 index pgfcheckcolorrange 255 mul round cvi put 3 index 1 3 index pgfcheckcolorrange 255 mul round cvi put 3 index 2 2 index pgfcheckcolorrange 255 mul round cvi put pop pop pop } bind def /pgfwritesamplegray { pgfcheckcolorrange 16777215 mul round cvi 1 index 0 2 index -16 bitshift put 1 index 1 2 index 65535 and -8 bitshift put 1 index 2 2 index 255 and put pop } bind def /pgfcheckcolorrange { dup 0.0 lt {pop 0.0} if dup 1.0 gt {pop 1.0} if } bind def /pgfchanneldepthcmyk 8 def /pgfchanneldepthrgb 8 def /pgfchanneldepthgray 24 def /pgfcolorsamplecmyk 4 string def /pgfcolorsamplergb 3 string def /pgfcolorsamplegray 3 string def /pgfrangecmyk [0 1 0 1 0 1 0 1] def /pgfrangergb [0 1 0 1 0 1] def /pgfrangegray [0 1] def /pgf1{gsave exec 1.0 pgfw 2.00002 0.0 moveto -6.00006 4.00005 lineto -3.00003 0.0 lineto -6.00006 -4.00005 lineto pgffill grestore} bind def /pgf2{gsave exec 1.0 pgfw 0.8 pgfw [ ] 0.0 setdash 1 setlinecap 1 setlinejoin -3.00003 4.00005 moveto -2.75002 2.50002 0.0 0.24998 0.75 0.0 curveto 0.0 -0.24998 -2.75002 -2.50002 -3.00003 -4.00005 curveto pgfstr grestore} bind def /pgf3{gsave exec 1.0 pgfw [ ] 0.0 setdash 0.0 -5.00005 moveto 0.0 5.00005 lineto pgfstr grestore} bind def /pgf4{gsave exec 1.0 pgfw [ ] 0.0 setdash -3.00003 -5.00005 moveto 0.0 -5.00005 lineto 0.0 5.00005 lineto -3.00003 5.00005 lineto pgfstr grestore} bind def /pgf5{gsave exec 1.0 pgfw [ ] 0.0 setdash -2.00002 -5.00005 moveto 1.0 -3.00003 1.0 3.00003 -2.00002 5.00005 curveto pgfstr grestore} bind def /pgf6{gsave exec 1.0 pgfw [ ] 0.0 setdash -4.50003 -5.00005 moveto 0.49998 0.0 lineto -4.50003 5.00005 lineto pgfstr grestore} bind def /pgf7{gsave exec 1.0 pgfw -2.50002 0.0 translate [ ] 0.0 setdash 3.00003 0.0 moveto 3.00003 1.65689 1.65689 3.00003 0.0 3.00003 curveto -1.65689 3.00003 -3.00003 1.65689 -3.00003 0.0 curveto -3.00003 -1.65689 -1.65689 -3.00003 0.0 -3.00003 curveto 1.65689 -3.00003 3.00003 -1.65689 3.00003 0.0 curveto closepath gsave pgffc pgffill grestore gsave pgfsc pgfstr grestore newpath grestore} bind def /pgf8{gsave exec 1.0 pgfw [ ] 0.0 setdash 1.0 0.0 moveto -5.00005 3.00003 lineto -11.00012 0.0 lineto -5.00005 -3.00003 lineto closepath gsave pgffc pgffill grestore gsave pgfsc pgfstr grestore newpath grestore} bind def @fedspecial end %%BeginFont: Roboto-Bold %!PS-AdobeFont-1.0: Roboto-Bold 2.001150; 2014 9 dict begin /FontName /Roboto-Bold def /FontInfo 9 dict dup begin /version (2.001150; 2014) readonly def /Notice (Copyright 2011 Google Inc. 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(\376\377\000E\000x\000a\000m\000p\000l\000e\000:\000\040\000F\000r\000e\000e\000\040\000E\000n\000e\000r\000g\000y\000\040\000C\000a\000l\000c\000u\000l\000a\000t\000i\000o\000n\000\040\000U\000s\000i\000n\000g\000\040\000P\000y\000t\000h\000o\000n) /OUT pdfmark end 109 -128 a 109 -128 a SDict begin [/Count -0/Dest (section*.71) cvn/Title (\376\377\000E\000n\000e\000r\000g\000y\000\040\000M\000i\000n\000i\000m\000i\000z\000a\000t\000i\000o\000n\000\040\000i\000n\000\040\000P\000r\000o\000t\000e\000i\000n\000\040\000F\000o\000l\000d\000i\000n\000g) /OUT pdfmark end 109 -128 a 109 -128 a SDict begin [/Count -0/Dest (section*.72) cvn/Title (\376\377\000E\000x\000a\000m\000p\000l\000e\000:\000\040\000E\000n\000e\000r\000g\000y\000\040\000M\000i\000n\000i\000m\000i\000z\000a\000t\000i\000o\000n\000\040\000U\000s\000i\000n\000g\000\040\000G\000R\000O\000M\000A\000C\000S) /OUT pdfmark end 109 -128 a 109 -128 a SDict begin [/Count -0/Dest (subsection.3.1.5) cvn/Title (\376\377\000S\000u\000m\000m\000a\000r\000y\000\040\000o\000f\000\040\000T\000r\000a\000d\000i\000t\000i\000o\000n\000a\000l\000\040\000A\000l\000g\000o\000r\000i\000t\000h\000m\000s) /OUT pdfmark end 109 -128 a 109 -128 a SDict begin [/Count -5/Dest (section.3.2) cvn/Title (\376\377\000M\000o\000d\000e\000r\000n\000\040\000M\000a\000c\000h\000i\000n\000e\000\040\000L\000e\000a\000r\000n\000i\000n\000g\000\040\000a\000n\000d\000\040\000D\000e\000e\000p\000\040\000L\000e\000a\000r\000n\000i\000n\000g\000\040\000M\000e\000t\000h\000o\000d\000s) /OUT pdfmark end 109 -128 a 109 -128 a SDict begin [/Count -1/Dest (subsection.3.2.1) cvn/Title (\376\377\000N\000e\000u\000r\000a\000l\000\040\000N\000e\000t\000w\000o\000r\000k\000s\000\040\000i\000n\000\040\000P\000r\000o\000t\000e\000i\000n\000\040\000P\000r\000e\000d\000i\000c\000t\000i\000o\000n) /OUT pdfmark end 109 -128 a 109 -128 a SDict begin [/Count -0/Dest (section*.73) cvn/Title (\376\377\000E\000x\000a\000m\000p\000l\000e\000:\000\040\000S\000i\000m\000p\000l\000e\000\040\000N\000e\000u\000r\000a\000l\000\040\000N\000e\000t\000w\000o\000r\000k\000\040\000f\000o\000r\000\040\000S\000e\000c\000o\000n\000d\000a\000r\000y\000\040\000S\000t\000r\000u\000c\000t\000u\000r\000e\000\040\000P\000r\000e\000d\000i\000c\000t\000i\000o\000n) /OUT pdfmark end 109 -128 a 109 -128 a SDict begin [/Count -4/Dest (subsection.3.2.2) cvn/Title (\376\377\000C\000o\000n\000v\000o\000l\000u\000t\000i\000o\000n\000a\000l\000\040\000N\000e\000u\000r\000a\000l\000\040\000N\000e\000t\000w\000o\000r\000k\000s\000\040\000a\000n\000d\000\040\000G\000r\000a\000p\000h\000\040\000N\000e\000u\000r\000a\000l\000\040\000N\000e\000t\000w\000o\000r\000k\000s) /OUT pdfmark end 109 -128 a 109 -128 a SDict begin [/Count -0/Dest (section*.74) cvn/Title 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109 -128 a 109 -128 a SDict begin [/Count -0/Dest (section*.78) cvn/Title (\376\377\000V\000a\000r\000i\000a\000t\000i\000o\000n\000a\000l\000\040\000A\000u\000t\000o\000e\000n\000c\000o\000d\000e\000r\000s\000\040\000\050\000V\000A\000E\000s\000\051\000\040\000f\000o\000r\000\040\000P\000r\000o\000t\000e\000i\000n\000\040\000D\000e\000s\000i\000g\000n) /OUT pdfmark end 109 -128 a 109 -128 a SDict begin [/Count -0/Dest (section*.79) cvn/Title (\376\377\000E\000x\000a\000m\000p\000l\000e\000:\000\040\000U\000s\000i\000n\000g\000\040\000a\000\040\000V\000A\000E\000\040\000f\000o\000r\000\040\000P\000r\000o\000t\000e\000i\000n\000\040\000S\000e\000q\000u\000e\000n\000c\000e\000\040\000G\000e\000n\000e\000r\000a\000t\000i\000o\000n) /OUT pdfmark end 109 -128 a 109 -128 a SDict begin [/Count -0/Dest (section*.80) cvn/Title 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pdfmark end 109 -128 a 109 -128 a SDict begin [/Count -0/Dest (section*.118) cvn/Title (\376\377\000F\000r\000a\000m\000e\000\040\000R\000e\000p\000r\000e\000s\000e\000n\000t\000a\000t\000i\000o\000n\000s) /OUT pdfmark end 109 -128 a 109 -128 a SDict begin [/Count -1/Dest (subsection.5.1.3) cvn/Title (\376\377\000S\000i\000d\000e\000\040\000C\000h\000a\000i\000n\000\040\000P\000r\000e\000d\000i\000c\000t\000i\000o\000n\000:\000\040\000A\000d\000d\000i\000n\000g\000\040\000t\000h\000e\000\040\000F\000u\000n\000c\000t\000i\000o\000n\000a\000l\000\040\000E\000l\000e\000m\000e\000n\000t\000s) /OUT pdfmark end 109 -128 a 109 -128 a SDict begin [/Count -0/Dest (section*.119) cvn/Title (\376\377\000C\000h\000a\000l\000l\000e\000n\000g\000e\000s\000\040\000i\000n\000\040\000S\000i\000d\000e\000\040\000C\000h\000a\000i\000n\000\040\000P\000r\000e\000d\000i\000c\000t\000i\000o\000n) /OUT pdfmark end 109 -128 a 109 -128 a SDict begin [/Count -1/Dest (subsection.5.1.4) cvn/Title 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y(sequences)d(in)h(such)f(a)h (wa)o(y)h(that)f(r)o(egions)f(of)h(similarity)h(ar)o(e)f(highlighted.) 32 b(These)24 b(r)o(egions)f(of)h(similarity)g(often)109 1834 y(indicate)e(ev)o(olutionar)q(y)i(r)o(elationships)e(and)g(shar)o (ed)g(functional)h(or)g(structur)n(al)g(r)o(oles)g(between)f(the)g (sequences.)109 1959 y(By)i(comparing)g(a)g(tar)o(get)g(pr)o(otein)g (sequence)g(t)o(o)h(a)f(set)g(of)g(r)o(elated)h(sequences)e(fr)o(om)i (other)f(or)o(ganisms,)h(MSAs)109 2083 y(can)20 b(pr)o(o)o(vide)g (insights)f(int)o(o)h(which)g(amino)g(acids)g(ar)o(e)g(impor)r(tant)g (for)g(the)g(structur)o(e)g(or)g(function)g(of)g(the)g(pr)o(otein.)233 2212 y Fu(Example:)k(Aligning)e(Sequences)f(Using)g(MSA)233 2341 y Fy(Suppose)26 b(we)g(ha)o(ve)g(sever)n(al)g(pr)o(otein)g (sequences)g(that)g(ar)o(e)g(homologous)h(t)o(o)f(a)h(tar)o(get)f(pr)o (otein.)41 b(The)26 b(MSA)109 2466 y(pr)o(ocess)20 b(will)h(align)f (these)g(sequences)g(t)o(o)h(r)o(eveal)f(conser)q(ved)g(r)o(esidues:) 109 2642 y SDict begin H.S end 109 2642 a 109 2642 a SDict begin 15 H.A end 109 2642 a 109 2642 a SDict begin [/View [/XYZ H.V]/Dest (lstlisting.5.-51) cvn /DEST pdfmark end 109 2642 a 0 TeXcolorgray 0 TeXcolorgray 0 TeXcolorgray 0.97 0.97 0.97 TeXcolorrgb 81 2661 3740 29 v 0 TeXcolorgray 0.97 0.97 0.97 TeXcolorrgb 0 TeXcolorgray 0.6 0.6 0.6 TeXcolorrgb 80 2661 4 29 v 81 2636 29 4 v 109 2636 3683 4 v 3792 2636 29 4 v 3816 2661 4 29 v 0 TeXcolorgray 0.6 0.6 0.6 TeXcolorrgb 0.97 0.97 0.97 TeXcolorrgb 84 2775 25 115 v 0.6 0.6 0.6 TeXcolorrgb 0.97 0.97 0.97 TeXcolorrgb 80 2775 4 115 v 0.6 0.6 0.6 TeXcolorrgb 80 2775 V 0.97 0.97 0.97 TeXcolorrgb 109 2775 3683 115 v 0.6 0.6 0.6 TeXcolorrgb 0.97 0.97 0.97 TeXcolorrgb 3791 2775 25 115 v 0.6 0.6 0.6 TeXcolorrgb 0.97 0.97 0.97 TeXcolorrgb 3816 2775 4 115 v 0.6 0.6 0.6 TeXcolorrgb 3816 2775 V 0 TeXcolorgray 109 2740 a SDict begin H.S end 109 2740 a 109 2740 a SDict begin 13.75 H.A end 109 2740 a 109 2740 a SDict begin [/View [/XYZ H.V]/Dest (lstnumber.-51.1) cvn /DEST pdfmark end 109 2740 a Fm(Sequence)k(1:)j(A)-6 b(TGC--)o(T)g(A)n(CGA)g(T)p 0.6 0.6 0.6 TeXcolorrgb 0.97 0.97 0.97 TeXcolorrgb 84 2889 25 115 v 0.6 0.6 0.6 TeXcolorrgb 0.97 0.97 0.97 TeXcolorrgb 80 2889 4 115 v 0.6 0.6 0.6 TeXcolorrgb 80 2889 V 0.97 0.97 0.97 TeXcolorrgb 109 2889 3683 115 v 0.6 0.6 0.6 TeXcolorrgb 0.97 0.97 0.97 TeXcolorrgb 3791 2889 25 115 v 0.6 0.6 0.6 TeXcolorrgb 0.97 0.97 0.97 TeXcolorrgb 3816 2889 4 115 v 0.6 0.6 0.6 TeXcolorrgb 3816 2889 V 0 TeXcolorgray 109 2855 a SDict begin H.S end 109 2855 a 109 2855 a SDict begin 13.75 H.A end 109 2855 a 109 2855 a SDict begin [/View [/XYZ H.V]/Dest (lstnumber.-51.2) cvn /DEST pdfmark end 109 2855 a Fm(Sequence)24 b(2:)j(A)-6 b(TGCTGT)g(A)q(-GA)g(T)p 0.6 0.6 0.6 TeXcolorrgb 0.97 0.97 0.97 TeXcolorrgb 84 3003 25 115 v 0.6 0.6 0.6 TeXcolorrgb 0.97 0.97 0.97 TeXcolorrgb 80 3003 4 115 v 0.6 0.6 0.6 TeXcolorrgb 80 3003 V 0.97 0.97 0.97 TeXcolorrgb 109 3003 3683 115 v 0.6 0.6 0.6 TeXcolorrgb 0.97 0.97 0.97 TeXcolorrgb 3791 3003 25 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b(TGCGT)q(-)o(A)n(CGA)g(T)p 0.97 0.97 0.97 TeXcolorrgb 81 3145 3740 29 v 0 TeXcolorgray 0.97 0.97 0.97 TeXcolorrgb 0 TeXcolorgray 0.6 0.6 0.6 TeXcolorrgb 80 3145 4 29 v 81 3145 29 4 v 109 3145 3683 4 v 3792 3145 29 4 v 3816 3145 4 29 v 0 TeXcolorgray 0 TeXcolorgray 0 TeXcolorgray 0 TeXcolorgray 233 3400 a Fy(In)24 b(this)f(example,)h (the)f(MSA)h(r)o(eveals)e(that)i(some)f(r)o(esidues,)g(such)g(as)h(the) f(positions)g(containing)g(")-5 b(A)g(T)o(GC")24 b(at)109 3525 y(the)c(star)r(t,)h(ar)o(e)g(conser)q(ved)g(acr)o(oss)g(all)g (four)g(sequences.)j(These)c(conser)q(ved)h(r)o(esidues)f(ma)o(y)h(pla) o(y)g(a)g(crucial)h(r)o(ole)109 3649 y(in)e(the)g(structur)o(e)h(or)g (function)f(of)h(the)f(pr)o(otein.)109 3831 y SDict begin H.S end 109 3831 a 109 3831 a SDict begin 15 H.A end 109 3831 a 109 3831 a SDict begin [/View [/XYZ H.V]/Dest (subsection.5.3.2) cvn /DEST pdfmark end 109 3831 a 133 x Fr(5.3.2)99 b(How)26 b(AlphaF)o(old2)g(Uses)f(MSA)g(Information)109 4163 y Fy(AlphaF)o(old2)18 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y(that)c(these)g(r)o(egions)g(form)h(impor)r(tant) f(structur)n(al)h(or)g(functional)f(units.)109 4955 y SDict begin H.S end 109 4955 a 109 4955 a SDict begin 15 H.A end 109 4955 a 109 4955 a SDict begin [/View [/XYZ H.V]/Dest (section*.124) cvn /DEST pdfmark end 109 4955 a Fu(E)o(v)o(olutionar)q(y)h(Couplings)109 5154 y Fy(E)o(v)o(olutionar) q(y)28 b(couplings)e(r)o(ef)o(er)i(t)o(o)f(pairs)g(of)g(amino)g(acids)g (that)g(tend)g(t)o(o)h(mutate)e(t)o(ogether)h(o)o(ver)h(ev)o(olutionar) q(y)109 5278 y(time.)22 b(This)c(co-ev)o(olution)h(suggests)c(that)j (the)f(amino)h(acids)f(ar)o(e)h(functionally)g(or)g(structur)n(ally)h (r)o(elated,)g(often)e(be-)109 5403 y(cause)h(they)f(form)i(par)r(t)f (of)g(the)g(same)g(structur)n(al)g(motif)h(or)f(ar)o(e)h(inv)o(olved)f (in)g(the)g(same)g(biochemical)h(inter)n(action.)109 5528 y(F)o(or)d(example,)g(if)g(two)h(r)o(esidues)e(ar)o(e)h(fr)o (equently)g(obser)q(ved)f(t)o(o)i(mutate)e(in)h(tandem)f(acr)o(oss)i (diff)o(er)o(ent)e(species,)h(it)g(is)p 0 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109 679 a 128 x Fr(6.4.4)99 b(Conclusion)109 997 y Fy(Pr)n(actical)32 b(pr)o(otein)e(design)f(is)h(a)h(multifaceted)f(pr)o(ocess)g(that)g (combines)g(computational)g(t)o(ools)h(with)g(experi-)109 1122 y(mental)22 b(v)o(alidation.)29 b(By)22 b(de\037ning)f(the)h(tar)o (get)h(function,)f(gener)n(ating)g(a)g(sequence,)h(optimizing)e(the)h (design,)g(and)109 1246 y(v)o(alidating)f(the)g(pr)o(otein)h (experimentally)l(,)f(r)o(esear)o(chers)h(can)f(cr)o(eate)h(pr)o (oteins)g(with)f(tailor)o(ed)h(pr)o(oper)r(ties)f(for)h(use)109 1371 y(in)h(r)o(esear)o(ch,)i(industr)q(y)l(,)f(and)f(medicine.)33 b(With)23 b(the)h(right)f(t)o(ools)h(and)f(str)n(ategies,)i(even)d (beginners)g(can)i(star)r(t)g(de-)109 1496 y(signing)15 b(functional)i(pr)o(oteins)f(and)g(contributing)g(t)o(o)h(adv)o (ancements)g(in)f(biotechnology)h(and)f(synthetic)h(biology)l(.)p 0 TeXcolorgray 0 TeXcolorgray eop end end %%Page: 122 122 TeXDict begin HPSdict begin 122 121 bop 0 TeXcolorgray 0 0 a SDict begin /product where{pop 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