TY - JOUR T1 - Prediction of Mutational Tolerance in HIV-1 Protease and Reverse Transcriptase Using Flexible Backbone Protein Design A1 - Humphris-Narayanan, Elisabeth A1 - Akiva, Eyal A1 - Varela, Rocco A1 - Ó Conchúir, Shane A1 - Kortemme, Tanja Y1 - 2012/08/23 N2 - Author Summary Many related protein sequences can be consistent with the structure and function of a given protein, suggesting that proteins may be quite robust to mutations. This tolerance to mutations is frequently exploited by pathogens. In particular, pathogens can rapidly evolve mutated proteins that have a new function - resistance against a therapeutic inhibitor - without abandoning other functions essential for the pathogen. This principle may also hold more generally: Proteins tolerant to mutational changes can more easily acquire new functions while maintaining their existing properties. The ability to predict the tolerance of proteins to mutation could thus help both to analyze the emergence of resistance mutations in pathogens and to engineer proteins with new functions. Here we develop a computational model to predict protein mutational tolerance towards point mutations accessible by single nucleotide changes, and validate it using two important pathogenic proteins and therapeutic targets: the protease and reverse transcriptase from HIV-1. The model provides insights into how resistance emerges and makes testable predictions on mutations that have not been seen yet. Similar models of mutational tolerance should be useful for characterizing and reengineering the functions of other proteins for which a three-dimensional structure is available. JF - PLOS Computational Biology JA - PLOS Computational Biology VL - 8 IS - 8 UR - https://doi.org/10.1371/journal.pcbi.1002639 SP - e1002639 EP - PB - Public Library of Science M3 - doi:10.1371/journal.pcbi.1002639 ER -