Journal Article

Prediction of Mutational Tolerance in HIV-1 Protease and Reverse Transcriptase Using Flexible Backbone Protein Design

Kortemme, Tanja, Akiva, Eyal, Varela, Rocco, Ó Conchúir, Shane, Humphris-Narayanan, Elisabeth

2012

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Biology / Computational biology / Development and progression / Gene mutations / Genetic aspects / Genetic transcription / Health aspects / HIV / HIV (Viruses) / HIV Protease - chemistry / HIV Protease - genetics / HIV Reverse Transcriptase - chemistry / HIV Reverse Transcriptase - genetics / Human immunodeficiency virus / Models, Molecular / Mutation / Physiological aspects / Protein Conformation / Proteins / Signs