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A thermodynamic model of protein structure evolution explains empirical amino acid substitution matrices

Norn, Christoffer LU ; André, Ingemar LU orcid and Theobald, Douglas L. (2021) In Protein Science 30(10). p.2057-2068
Abstract

Proteins evolve under a myriad of biophysical selection pressures that collectively control the patterns of amino acid substitutions. These evolutionary pressures are sufficiently consistent over time and across protein families to produce substitution patterns, summarized in global amino acid substitution matrices such as BLOSUM, JTT, WAG, and LG, which can be used to successfully detect homologs, infer phylogenies, and reconstruct ancestral sequences. Although the factors that govern the variation of amino acid substitution rates have received much attention, the influence of thermodynamic stability constraints remains unresolved. Here we develop a simple model to calculate amino acid substitution matrices from evolutionary dynamics... (More)

Proteins evolve under a myriad of biophysical selection pressures that collectively control the patterns of amino acid substitutions. These evolutionary pressures are sufficiently consistent over time and across protein families to produce substitution patterns, summarized in global amino acid substitution matrices such as BLOSUM, JTT, WAG, and LG, which can be used to successfully detect homologs, infer phylogenies, and reconstruct ancestral sequences. Although the factors that govern the variation of amino acid substitution rates have received much attention, the influence of thermodynamic stability constraints remains unresolved. Here we develop a simple model to calculate amino acid substitution matrices from evolutionary dynamics controlled by a fitness function that reports on the thermodynamic effects of amino acid mutations in protein structures. This hybrid biophysical and evolutionary model accounts for nucleotide transition/transversion rate bias, multi-nucleotide codon changes, the number of codons per amino acid, and thermodynamic protein stability. We find that our theoretical model accurately recapitulates the complex yet universal pattern observed in common global amino acid substitution matrices used in phylogenetics. These results suggest that selection for thermodynamically stable proteins, coupled with nucleotide mutation bias filtered by the structure of the genetic code, is the primary driver behind the global amino acid substitution patterns observed in proteins throughout the tree of life.

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author
; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
amino acid substitution, exchangeabilities, protein evolution, protein stability, replacement matrices
in
Protein Science
volume
30
issue
10
pages
2057 - 2068
publisher
The Protein Society
external identifiers
  • pmid:34218472
  • scopus:85111553639
ISSN
0961-8368
DOI
10.1002/pro.4155
language
English
LU publication?
yes
additional info
Funding Information: CN and IA was supported by a grant from the Swedish Research Council (2015‐04203). DLT was supported by NIH grants R01GM096053 and R01GM132499. Publisher Copyright: © 2021 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
id
39e7591e-4a75-4dfe-814d-f44fcb947fb1
date added to LUP
2021-08-30 15:44:36
date last changed
2025-01-26 14:29:22
@article{39e7591e-4a75-4dfe-814d-f44fcb947fb1,
  abstract     = {{<p>Proteins evolve under a myriad of biophysical selection pressures that collectively control the patterns of amino acid substitutions. These evolutionary pressures are sufficiently consistent over time and across protein families to produce substitution patterns, summarized in global amino acid substitution matrices such as BLOSUM, JTT, WAG, and LG, which can be used to successfully detect homologs, infer phylogenies, and reconstruct ancestral sequences. Although the factors that govern the variation of amino acid substitution rates have received much attention, the influence of thermodynamic stability constraints remains unresolved. Here we develop a simple model to calculate amino acid substitution matrices from evolutionary dynamics controlled by a fitness function that reports on the thermodynamic effects of amino acid mutations in protein structures. This hybrid biophysical and evolutionary model accounts for nucleotide transition/transversion rate bias, multi-nucleotide codon changes, the number of codons per amino acid, and thermodynamic protein stability. We find that our theoretical model accurately recapitulates the complex yet universal pattern observed in common global amino acid substitution matrices used in phylogenetics. These results suggest that selection for thermodynamically stable proteins, coupled with nucleotide mutation bias filtered by the structure of the genetic code, is the primary driver behind the global amino acid substitution patterns observed in proteins throughout the tree of life.</p>}},
  author       = {{Norn, Christoffer and André, Ingemar and Theobald, Douglas L.}},
  issn         = {{0961-8368}},
  keywords     = {{amino acid substitution; exchangeabilities; protein evolution; protein stability; replacement matrices}},
  language     = {{eng}},
  number       = {{10}},
  pages        = {{2057--2068}},
  publisher    = {{The Protein Society}},
  series       = {{Protein Science}},
  title        = {{A thermodynamic model of protein structure evolution explains empirical amino acid substitution matrices}},
  url          = {{http://dx.doi.org/10.1002/pro.4155}},
  doi          = {{10.1002/pro.4155}},
  volume       = {{30}},
  year         = {{2021}},
}