Selection maintaining protein stability at equilibrium

DOI10.1016/J.JTBI.2015.12.001zbMATH Open1343.92386arXiv1512.08913OpenAlexW2801590312WikidataQ86930204 ScholiaQ86930204MaRDI QIDQ304847FDOQ304847

Authors: Sanzo Miyazawa

Publication date: 26 August 2016

Published in: Journal of Theoretical Biology (Search for Journal in Brave)

Abstract: The common understanding of protein evolution has been that neutral or slightly deleterious mutations are fixed by random drift, and evolutionary rate is determined primarily by the proportion of neutral mutations. However, recent studies have revealed that highly expressed genes evolve slowly because of fitness costs due to misfolded proteins. Here we study selection maintaining protein stability. Protein fitness is taken to be

, where

s

and

D e l t a D e l t a G

are selective advantage and stability change of a mutant protein,

D e l t a G

is the folding free energy of the wild-type protein, and

k a p p a

represents protein abundance and indispensability. The distribution of

D e l t a D e l t a G

is approximated to be a bi-Gaussian function, which represents structurally slightly- or highly-constrained sites. Also, the mean of the distribution is negatively proportional to

D e l t a G

. The evolution of this gene has an equilibrium (

D e l t a G_{e}

) of protein stability, the range of which is consistent with experimental values. The probability distribution of

K_{a} / K_{s}

, the ratio of nonsynonymous to synonymous substitution rate per site, over fixed mutants in the vicinity of the equilibrium shows that nearly neutral selection is predominant only in low-abundant, non-essential proteins of

D e l t a G_{e} > - 2.5

kcal/mol. In the other proteins, positive selection on stabilizing mutations is significant to maintain protein stability at equilibrium as well as random drift on slightly negative mutations, although the average