Inferring Stabilizing Mutations from Protein Phylogenies: Application to Influenza Hemagglutinin

被引:49
作者
Bloom, Jesse D. [1 ]
Glassman, Matthew J. [1 ]
机构
[1] CALTECH, Div Biol, Pasadena, CA 91125 USA
关键词
COLI RIBONUCLEASE HI; AMINO-ACID SUBSTITUTIONS; TEMPERATURE-SENSITIVE MUTANTS; MULTIPLE SEQUENCE ALIGNMENT; ESCHERICHIA-COLI; SHOCK PROTEIN; DIRECTED EVOLUTION; SECONDARY STRUCTURE; HYDROPHOBIC CORE; POINT MUTATIONS;
D O I
10.1371/journal.pcbi.1000349
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
One selection pressure shaping sequence evolution is the requirement that a protein fold with sufficient stability to perform its biological functions. We present a conceptual framework that explains how this requirement causes the probability that a particular amino acid mutation is fixed during evolution to depend on its effect on protein stability. We mathematically formalize this framework to develop a Bayesian approach for inferring the stability effects of individual mutations from homologous protein sequences of known phylogeny. This approach is able to predict published experimentally measured mutational stability effects (Delta Delta G values) with an accuracy that exceeds both a state-of-the-art physicochemical modeling program and the sequence-based consensus approach. As a further test, we use our phylogenetic inference approach to predict stabilizing mutations to influenza hemagglutinin. We introduce these mutations into a temperature-sensitive influenza virus with a defect in its hemagglutinin gene and experimentally demonstrate that some of the mutations allow the virus to grow at higher temperatures. Our work therefore describes a powerful new approach for predicting stabilizing mutations that can be successfully applied even to large, complex proteins such as hemagglutinin. This approach also makes a mathematical link between phylogenetics and experimentally measurable protein properties, potentially paving the way for more accurate analyses of molecular evolution.
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页数:19
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