Protein WISDOM: A Workbench für

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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

Das Ziel der de novo-Protein-Design ist es, die Aminosäure-Sequenzen, die in eine gewünschte 3-dimensionale Struktur mit Verbesserungen in spezifischen Eigenschaften, wie Bindungsaffinität, Agonisten oder Antagonisten Verhalten oder Stabilität gegenüber der nativen Sequenz zu falten finden. Protein-Design liegt in der Mitte der aktuellen Fortschritte Drug Design und Entdeckung. Nicht nur, dass Protein-Design liefern Vorhersagen für potenziell nützliche drug targets, aber es verbessert auch unser Verständnis der Proteinfaltung Prozess-und Protein-Protein-Interaktionen. Experimentelle Methoden wie die gerichtete Evolution haben Erfolg in Protein-Design gezeigt. Allerdings sind solche Verfahren durch den begrenzten Raum-Sequenz, die tractably gesucht werden kann begrenzt. Im Gegensatz dazu erlauben Computational Design-Strategien für das Screening von einer viel größeren Menge von Sequenzen, die eine breite Vielfalt von Eigenschaften und Funktionalität. Wir haben eine Reihe von Computer-de novo Protein-Design entwickelte methods fähig Bewältigung mehrere wichtige Bereiche der Protein-Design. Dazu gehören die Gestaltung von monomeren Proteinen für erhöhte Stabilität und Komplexe für erhöhte Bindungsaffinität.

Um diese Methoden für eine breitere Verbreitung verwenden wir präsentieren Protein WISDOM ( http://www.proteinwisdom.org ), ein Werkzeug, das automatisierte Verfahren bietet für eine Vielzahl von Protein-Design-Probleme. Strukturelle Vorlagen eingereicht werden, um den Design-Prozess zu initialisieren. Die erste Stufe der Konstruktion ist eine Optimierung Sequenz Auswahlstufe, die auf die Verbesserung der Stabilität durch Minimierung der potentiellen Energie in dem Sequenzraum soll. Ausgewählte Sequenzen werden dann durch einen Falz Spezifität Stufe und einer Bindungsaffinität Stufe laufen. Ein Rang geordnete Liste der Sequenzen für jeden Schritt des Verfahrens, mit entsprechenden vorbestimmten Strukturen, bietet dem Benutzer eine umfassende quantitative Bewertung der Konstruktion. Hier bieten wir Ihnen die Details of jedes Design-Methode, sowie einige bemerkenswerte experimentelle Erfolge durch den Einsatz der Methoden erreicht.

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