Predicting the tolerated sequences for proteins and protein interfaces using RosettaBackrub flexible backbone design.

Predicting the set of sequences that are tolerated by a protein or protein interface, while maintaining a desired function, is useful for characterizing protein interaction specificity and for computationally designing sequence libraries to engineer proteins with new functions. Here we provide a gen...

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Autores principales:	Colin A Smith, Tanja Kortemme
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8fb7179c113f4eaaa4290447282935da
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spelling	oai:doaj.org-article:8fb7179c113f4eaaa4290447282935da2021-11-18T06:50:09ZPredicting the tolerated sequences for proteins and protein interfaces using RosettaBackrub flexible backbone design.1932-620310.1371/journal.pone.0020451https://doaj.org/article/8fb7179c113f4eaaa4290447282935da2011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21789164/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Predicting the set of sequences that are tolerated by a protein or protein interface, while maintaining a desired function, is useful for characterizing protein interaction specificity and for computationally designing sequence libraries to engineer proteins with new functions. Here we provide a general method, a detailed set of protocols, and several benchmarks and analyses for estimating tolerated sequences using flexible backbone protein design implemented in the Rosetta molecular modeling software suite. The input to the method is at least one experimentally determined three-dimensional protein structure or high-quality model. The starting structure(s) are expanded or refined into a conformational ensemble using Monte Carlo simulations consisting of backrub backbone and side chain moves in Rosetta. The method then uses a combination of simulated annealing and genetic algorithm optimization methods to enrich for low-energy sequences for the individual members of the ensemble. To emphasize certain functional requirements (e.g. forming a binding interface), interactions between and within parts of the structure (e.g. domains) can be reweighted in the scoring function. Results from each backbone structure are merged together to create a single estimate for the tolerated sequence space. We provide an extensive description of the protocol and its parameters, all source code, example analysis scripts and three tests applying this method to finding sequences predicted to stabilize proteins or protein interfaces. The generality of this method makes many other applications possible, for example stabilizing interactions with small molecules, DNA, or RNA. Through the use of within-domain reweighting and/or multistate design, it may also be possible to use this method to find sequences that stabilize particular protein conformations or binding interactions over others.Colin A SmithTanja KortemmePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 7, p e20451 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Colin A Smith Tanja Kortemme Predicting the tolerated sequences for proteins and protein interfaces using RosettaBackrub flexible backbone design.
description	Predicting the set of sequences that are tolerated by a protein or protein interface, while maintaining a desired function, is useful for characterizing protein interaction specificity and for computationally designing sequence libraries to engineer proteins with new functions. Here we provide a general method, a detailed set of protocols, and several benchmarks and analyses for estimating tolerated sequences using flexible backbone protein design implemented in the Rosetta molecular modeling software suite. The input to the method is at least one experimentally determined three-dimensional protein structure or high-quality model. The starting structure(s) are expanded or refined into a conformational ensemble using Monte Carlo simulations consisting of backrub backbone and side chain moves in Rosetta. The method then uses a combination of simulated annealing and genetic algorithm optimization methods to enrich for low-energy sequences for the individual members of the ensemble. To emphasize certain functional requirements (e.g. forming a binding interface), interactions between and within parts of the structure (e.g. domains) can be reweighted in the scoring function. Results from each backbone structure are merged together to create a single estimate for the tolerated sequence space. We provide an extensive description of the protocol and its parameters, all source code, example analysis scripts and three tests applying this method to finding sequences predicted to stabilize proteins or protein interfaces. The generality of this method makes many other applications possible, for example stabilizing interactions with small molecules, DNA, or RNA. Through the use of within-domain reweighting and/or multistate design, it may also be possible to use this method to find sequences that stabilize particular protein conformations or binding interactions over others.
format	article
author	Colin A Smith Tanja Kortemme
author_facet	Colin A Smith Tanja Kortemme
author_sort	Colin A Smith
title	Predicting the tolerated sequences for proteins and protein interfaces using RosettaBackrub flexible backbone design.
title_short	Predicting the tolerated sequences for proteins and protein interfaces using RosettaBackrub flexible backbone design.
title_full	Predicting the tolerated sequences for proteins and protein interfaces using RosettaBackrub flexible backbone design.
title_fullStr	Predicting the tolerated sequences for proteins and protein interfaces using RosettaBackrub flexible backbone design.
title_full_unstemmed	Predicting the tolerated sequences for proteins and protein interfaces using RosettaBackrub flexible backbone design.
title_sort	predicting the tolerated sequences for proteins and protein interfaces using rosettabackrub flexible backbone design.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/8fb7179c113f4eaaa4290447282935da
work_keys_str_mv	AT colinasmith predictingthetoleratedsequencesforproteinsandproteininterfacesusingrosettabackrubflexiblebackbonedesign AT tanjakortemme predictingthetoleratedsequencesforproteinsandproteininterfacesusingrosettabackrubflexiblebackbonedesign
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Predicting the tolerated sequences for proteins and protein interfaces using RosettaBackrub flexible backbone design.

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