Prediction of mutational tolerance in HIV-1 protease and reverse transcriptase using flexible backbone protein design.

Predicting which mutations proteins tolerate while maintaining their structure and function has important applications for modeling fundamental properties of proteins and their evolution; it also drives progress in protein design. Here we develop a computational model to predict the tolerated sequen...

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Autores principales:	Elisabeth Humphris-Narayanan, Eyal Akiva, Rocco Varela, Shane Ó Conchúir, Tanja Kortemme
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/19eaeda4c66a420a902d5cc7848c00e9
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spelling	oai:doaj.org-article:19eaeda4c66a420a902d5cc7848c00e92021-11-18T05:51:04ZPrediction of mutational tolerance in HIV-1 protease and reverse transcriptase using flexible backbone protein design.1553-734X1553-735810.1371/journal.pcbi.1002639https://doaj.org/article/19eaeda4c66a420a902d5cc7848c00e92012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22927804/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Predicting which mutations proteins tolerate while maintaining their structure and function has important applications for modeling fundamental properties of proteins and their evolution; it also drives progress in protein design. Here we develop a computational model to predict the tolerated sequence space of HIV-1 protease reachable by single mutations. We assess the model by comparison to the observed variability in more than 50,000 HIV-1 protease sequences, one of the most comprehensive datasets on tolerated sequence space. We then extend the model to a second protein, reverse transcriptase. The model integrates multiple structural and functional constraints acting on a protein and uses ensembles of protein conformations. We find the model correctly captures a considerable fraction of protease and reverse-transcriptase mutational tolerance and shows comparable accuracy using either experimentally determined or computationally generated structural ensembles. Predictions of tolerated sequence space afforded by the model provide insights into stability-function tradeoffs in the emergence of resistance mutations and into strengths and limitations of the computational model.Elisabeth Humphris-NarayananEyal AkivaRocco VarelaShane Ó ConchúirTanja KortemmePublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 8, Iss 8, p e1002639 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Elisabeth Humphris-Narayanan Eyal Akiva Rocco Varela Shane Ó Conchúir Tanja Kortemme Prediction of mutational tolerance in HIV-1 protease and reverse transcriptase using flexible backbone protein design.
description	Predicting which mutations proteins tolerate while maintaining their structure and function has important applications for modeling fundamental properties of proteins and their evolution; it also drives progress in protein design. Here we develop a computational model to predict the tolerated sequence space of HIV-1 protease reachable by single mutations. We assess the model by comparison to the observed variability in more than 50,000 HIV-1 protease sequences, one of the most comprehensive datasets on tolerated sequence space. We then extend the model to a second protein, reverse transcriptase. The model integrates multiple structural and functional constraints acting on a protein and uses ensembles of protein conformations. We find the model correctly captures a considerable fraction of protease and reverse-transcriptase mutational tolerance and shows comparable accuracy using either experimentally determined or computationally generated structural ensembles. Predictions of tolerated sequence space afforded by the model provide insights into stability-function tradeoffs in the emergence of resistance mutations and into strengths and limitations of the computational model.
format	article
author	Elisabeth Humphris-Narayanan Eyal Akiva Rocco Varela Shane Ó Conchúir Tanja Kortemme
author_facet	Elisabeth Humphris-Narayanan Eyal Akiva Rocco Varela Shane Ó Conchúir Tanja Kortemme
author_sort	Elisabeth Humphris-Narayanan
title	Prediction of mutational tolerance in HIV-1 protease and reverse transcriptase using flexible backbone protein design.
title_short	Prediction of mutational tolerance in HIV-1 protease and reverse transcriptase using flexible backbone protein design.
title_full	Prediction of mutational tolerance in HIV-1 protease and reverse transcriptase using flexible backbone protein design.
title_fullStr	Prediction of mutational tolerance in HIV-1 protease and reverse transcriptase using flexible backbone protein design.
title_full_unstemmed	Prediction of mutational tolerance in HIV-1 protease and reverse transcriptase using flexible backbone protein design.
title_sort	prediction of mutational tolerance in hiv-1 protease and reverse transcriptase using flexible backbone protein design.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/19eaeda4c66a420a902d5cc7848c00e9
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Prediction of mutational tolerance in HIV-1 protease and reverse transcriptase using flexible backbone protein design.

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