title: Prediction of mutational tolerance in HIV-1 protease and reverse transcriptase using flexible backbone protein design.
abstract: 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.
authors.affiliation: Graduate Group in Biophysics, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Humphris-Narayanan
authors.forename: Eyal
authors.initials: E
authors.lastname: Akiva
authors.forename: Rocco
authors.initials: R
authors.lastname: Varela
authors.forename: Shane
authors.initials: S
authors.lastname: Ó Conchúir
authors.forename: Tanja
authors.initials: T
authors.lastname: Kortemme
mesh_terms: D016333:HIV Protease / Q000737:chemistry / Q000235:genetics*; D054303:HIV Reverse Transcriptase / Q000737:chemistry / Q000235:genetics*; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation
chemical_list: C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1