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

• DOI: 10.1371/journal.pcbi.1002639
• Publication Date: 2012-08-23T21:44:51Z
• Authors: Elisabeth Humphri...; Eyal Akiva; Rocco Varela; Shane Ó Conchúir; Tanja Kortemme
• Keywords: Models, Molecular; 0301 basic medicine; QH301-705.5; Protein Conformation; Molecular; HIV Reverse Transcriptase; 3. Good health; 03 medical and health sciences; HIV Protease; Models; 616; Mutation; Biology (General); Research Article

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.