UCL logo

UCL Discovery

UCL home » Library Services » Electronic resources » UCL Discovery

Sequence entropy of folding and the absolute rate of amino acid substitutions

Goldstein, R; Pollock, D; (2017) Sequence entropy of folding and the absolute rate of amino acid substitutions. Nature Ecology & Evolution , 1 pp. 1923-1930. 10.1038/s41559-017-0338-9. Green open access

[img]
Preview
Text
Goldstein_Sequence_entropy_folding_AAM.pdf - ["content_typename_Accepted version" not defined]

Download (1MB) | Preview

Abstract

Adequate representations of protein evolution should consider how the acceptance of mutations depends on the sequence context in which they arise. However, epistatic interactions among sites in a protein result in hererogeneities in the substitution rate, both temporal and spatial, that are beyond the capabilities of current models. Here we use parallels between amino acid substitutions and chemical reaction kinetics to develop an improved theory of protein evolution. We constructed a mechanistic framework for modelling amino acid substitution rates that uses the formalisms of statistical mechanics, with principles of population genetics underlying the analysis. Theoretical analyses and computer simulations of proteins under purifying selection for thermodynamic stability show that substitution rates and the stabilization of resident amino acids (the ‘evolutionary Stokes shift’) can be predicted from biophysics and the effect of sequence entropy alone. Furthermore, we demonstrate that substitutions predominantly occur when epistatic interactions result in near neutrality; substitution rates are determined by how often epistasis results in such nearly neutral conditions. This theory provides a general framework for modelling protein sequence change under purifying selection, potentially explains patterns of convergence and mutation rates in real proteins that are incompatible with previous models, and provides a better null model for the detection of adaptive changes.

Type: Article
Title: Sequence entropy of folding and the absolute rate of amino acid substitutions
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41559-017-0338-9
Publisher version: http://dx.doi.org/10.1038/s41559-017-0338-9
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: protein evolution, epistasis, coevolution, transition state theory, statistical mechanics, substitution rate, evolutionary Stokes shift, entrenchment, contingency
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
URI: http://discovery.ucl.ac.uk/id/eprint/10025852
Downloads since deposit
0Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item