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Biology

Protein visdom: En Workbench för Published: July 25, 2013 doi: 10.3791/50476
Automatic Translation
1, 1, 1, 1, 1
1Department of Chemical and Biological Engineering, Princeton University

Abstract

Syftet med de novo protein design är att hitta de aminosyrasekvenser som kommer att vika till en önskad 3-dimensionell struktur med förbättringar inom specifika egenskaper, såsom bindningsaffinitet, agonist eller antagonist beteende, eller stabilitet, i förhållande till den nativa sekvensen. Protein utformningen ligger i centrum för nuvarande framsteg läkemedelsdesign och upptäckt. Inte bara ger protein designen förutsägelser för potentiellt användbara målproteiner, men det ökar också vår förståelse av protein folding process-och protein-protein interaktioner. Experimentella metoder såsom riktad evolution har visat framgång i protein design. Men dessa metoder begränsas av knappa sekvensen utrymme som kan sökas tractably. Däremot computational design strategier möjliggöra screening av en mycket större uppsättning av sekvenser som täcker en mängd olika egenskaper och funktionalitet. Vi har utvecklat en rad computational de novo protein designen methods kapabla att hantera flera viktiga områden av protein design. Dessa inkluderar utformningen av monomera proteiner för ökad stabilitet och komplex för ökad bindningsaffinitet.

För att sprida dessa metoder för bredare användning presenterar vi Protein VISHETEN ( http://www.proteinwisdom.org ), ett verktyg som ger automatiserade metoder för en mängd olika problem proteinutformning. Strukturella mallar lämnas att initiera designprocessen. Den första etappen av design är en optimering sekvens urvalet som syftar till att förbättra stabiliteten genom minimering av potentiell energi i sekvensen rymden. Valda sekvenser körs sedan genom en vikning specificitet scen och en bindningsaffinitet skede. En rang ordnad lista av sekvenserna för varje steg i processen, tillsammans med relevanta utformade strukturer, ger användaren en heltäckande kvantitativ bedömning av designen. Här ger vi detaljerna of varje konstruktion metod, liksom flera uppmärksammade experimentella framgångar som uppnåtts genom användning av metoderna.

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Protein visdom: En Workbench för<em&gt; I silico</em&gt;<em&gt; De novo</em&gt; Design av biomolekyler
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Smadbeck, J., Peterson, M. B.,… More

Smadbeck, J., Peterson, M. B., Khoury, G. A., Taylor, M. S., Floudas, C. A. Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules. J. Vis. Exp. (77), e50476, doi:10.3791/50476 (2013).

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