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Inferring Stabilizing Mutations from Protein Phylogenies: Application to Influenza Hemagglutinin

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 ev...

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Detalles Bibliográficos
Autores principales: Bloom, Jesse D., Glassman, Matthew J.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2664478/
https://www.ncbi.nlm.nih.gov/pubmed/19381264
http://dx.doi.org/10.1371/journal.pcbi.1000349
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author Bloom, Jesse D.
Glassman, Matthew J.
author_facet Bloom, Jesse D.
Glassman, Matthew J.
author_sort Bloom, Jesse D.
collection PubMed
description 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 (ΔΔG 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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spelling pubmed-26644782009-04-17 Inferring Stabilizing Mutations from Protein Phylogenies: Application to Influenza Hemagglutinin Bloom, Jesse D. Glassman, Matthew J. PLoS Comput Biol Research Article 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 (ΔΔG 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. Public Library of Science 2009-04-17 /pmc/articles/PMC2664478/ /pubmed/19381264 http://dx.doi.org/10.1371/journal.pcbi.1000349 Text en Bloom, Glassman. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Bloom, Jesse D.
Glassman, Matthew J.
Inferring Stabilizing Mutations from Protein Phylogenies: Application to Influenza Hemagglutinin
title Inferring Stabilizing Mutations from Protein Phylogenies: Application to Influenza Hemagglutinin
title_full Inferring Stabilizing Mutations from Protein Phylogenies: Application to Influenza Hemagglutinin
title_fullStr Inferring Stabilizing Mutations from Protein Phylogenies: Application to Influenza Hemagglutinin
title_full_unstemmed Inferring Stabilizing Mutations from Protein Phylogenies: Application to Influenza Hemagglutinin
title_short Inferring Stabilizing Mutations from Protein Phylogenies: Application to Influenza Hemagglutinin
title_sort inferring stabilizing mutations from protein phylogenies: application to influenza hemagglutinin
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2664478/
https://www.ncbi.nlm.nih.gov/pubmed/19381264
http://dx.doi.org/10.1371/journal.pcbi.1000349
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