Proteïne WIJSHEID: Een Workbench voor

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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

Het doel van de novo eiwit ontwerp van de aminozuursequenties die vouwen in een gewenste 3-dimensionale structuur met een verbetering in bepaalde eigenschappen, zoals bindingsaffiniteit, agonist of antagonist gedrag of de stabiliteit ten opzichte van de natieve sequentie zijn. Eiwit ontwerp ligt in het centrum van de huidige vooruitgang drug design en ontdekking. Niet alleen proteïne ontwerp zorgen voorspellingen voor potentieel nuttige drug targets, maar het verbetert ook ons ​​begrip van het vouwen van eiwitten proces en eiwit-eiwit interacties. Experimentele methoden, zoals gerichte evolutie succesvol zijn gebleken in eiwit ontwerp. Echter dergelijke werkwijzen beperkt door de beperkte ruimte die tractably sequentie kan worden gezocht. Daarentegen computational ontwerpstrategieën kunnen voor het screenen van een veel grotere reeks van sequenties die een breed scala van eigenschappen en functionaliteit. We hebben een scala van computationele de novo eiwit ontwerp methodiek ontwikkeldds kan inspelen op een aantal belangrijke gebieden van het eiwit ontwerp. Deze omvatten het ontwerp van monomere eiwitten voor verhoogde stabiliteit en complexen voor verhoogde bindingsaffiniteit.

Om deze methoden te verspreiden voor bredere gebruiken we presenteren Protein WIJSHEID ( http://www.proteinwisdom.org ), een instrument dat geautomatiseerde methodes voorziet in een verscheidenheid van eiwitten ontwerpproblemen. Structurele templates worden voorgelegd aan het ontwerpproces te initialiseren. De eerste fase van het ontwerp is een optimalisatie opeenvolging selectiefase dat zich richt op het verbeteren van de stabiliteit door minimalisering van potentiële energie in de volgorde ruimte. Geselecteerde sequenties worden vervolgens door een vouw specificiteit podium en een bindingsaffiniteit podium. Een rank-geordende lijst van de reeksen voor elke stap van het proces, samen met relevante ontworpen structuren, biedt de gebruiker een uitgebreide kwantitatieve beoordeling van het ontwerp. Hier geven we de details of elk ontwerpmethode, evenals verscheidene opmerkelijke experimentele successen bereikt door het gebruik van de werkwijzen.

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