Atomistic simulation of protein evolution reveals sequence covariation and time-dependent fluctuations of site-specific substitution rates.
Journal
PLoS computational biology
ISSN: 1553-7358
Titre abrégé: PLoS Comput Biol
Pays: United States
ID NLM: 101238922
Informations de publication
Date de publication:
03 2023
03 2023
Historique:
received:
31
05
2022
accepted:
01
03
2023
revised:
05
04
2023
medline:
7
4
2023
pubmed:
25
3
2023
entrez:
24
3
2023
Statut:
epublish
Résumé
Thermodynamic stability is a crucial fitness constraint in protein evolution and is a central factor in shaping the sequence landscapes of proteins. The correlation between stability and molecular fitness depends on the mechanism that relates the biophysical property with biological function. In the simplest case, stability and fitness are related by the amount of folded protein. However, when proteins are toxic in the unfolded state, the fitness function shifts, resulting in higher stability under mutation-selection balance. Likewise, a higher population size results in a similar change in protein stability, as it magnifies the effect of the selection pressure in evolutionary dynamics. This study investigates how such factors affect the evolution of protein stability, site-specific mutation rates, and residue-residue covariation. To simulate evolutionary trajectories with realistic modeling of protein energetics, we develop an all-atom simulator of protein evolution, RosettaEvolve. By evolving proteins under different fitness functions, we can study how the fitness function affects the distribution of proposed and accepted mutations, site-specific rates, and the prevalence of correlated amino acid substitutions. We demonstrate that fitness pressure affects the proposal distribution of mutational effects, that changes in stability can largely explain variations in site-specific substitution rates in evolutionary trajectories, and that increased fitness pressure results in a stronger covariation signal. Our results give mechanistic insight into the evolutionary consequences of variation in protein stability and provide a basis to rationalize the strong covariation signal observed in natural sequence alignments.
Identifiants
pubmed: 36961827
doi: 10.1371/journal.pcbi.1010262
pii: PCOMPBIOL-D-22-00830
pmc: PMC10075473
doi:
Substances chimiques
Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1010262Informations de copyright
Copyright: © 2023 Norn, André. 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 credited.
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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