Proteine ​​saggezza: un banco di lavoro per

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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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Abstract

L'obiettivo di disegno de novo di proteine ​​è di trovare le sequenze amminoacidiche che si piega in una struttura 3-dimensionale desiderata con miglioramenti nelle proprietà specifiche, quali affinità di legame, agonista o antagonista comportamento, o stabilità, relativi alla sequenza nativa. Progettazione di proteine ​​si trova al centro del progresso attuale progettazione di farmaci e di scoperta. Non solo progettazione di proteine ​​fornisce previsioni per bersagli farmacologici potenzialmente utili, ma migliora anche la nostra comprensione del processo di folding delle proteine ​​e le interazioni proteina-proteina. Metodi sperimentali come evoluzione diretta hanno dato risultati positivi in ​​progettazione di proteine. Tuttavia, tali metodi sono limitate dallo spazio sequenza limitata che possono essere cercati trattabile. In contrasto, strategie di progettazione computazionali permettono la proiezione di un insieme più ampio di sequenze che coprono una vasta gamma di proprietà e funzionalità. Abbiamo sviluppato una serie di calcolo de novo di proteine ​​disegno metoDS in grado di affrontare diverse importanti aree di progettazione di proteine. Questi includono la progettazione di proteine ​​monomeriche per una maggiore stabilità e complessi per una maggiore affinità di legame.

Per diffondere questi metodi per il più ampio uso presentiamo SAGGEZZA Proteine ​​( http://www.proteinwisdom.org ), uno strumento che fornisce metodi automatici per una varietà di problemi di progettazione di proteine. Modelli strutturali sono state inoltrate per inizializzare il processo di progettazione. La prima fase di progettazione è una sequenza fase di selezione di ottimizzazione che mira a migliorare la stabilità mediante minimizzazione dell'energia potenziale nello spazio sequenza. Sequenze selezionate sono poi eseguiti attraverso una fase di specificità piega e una fase di affinità di legame. Una lista ordinata rango delle sequenze per ogni fase del processo, insieme con strutture progettate pertinenti, fornisce all'utente una valutazione quantitativa completa del disegno. Qui forniamo i dettagli of ciascun metodo di progettazione, così come diversi successi notevoli sperimentali ottenuti attraverso l'uso dei metodi.

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