Universal distribution of mutational effects on protein stability, uncoupling of protein robustness from sequence evolution and distinct evolutionary modes of prokaryotic and eukaryotic proteins

Abstract

Robustness to destabilizing effects of mutations is thought of as a key factor of protein evolution. The connections between two measures of robustness, the relative core size and the computationally estimated effect of mutations on protein stability (ΔΔG), protein abundance and the selection pressure on protein-coding genes (dN/dS) were analyzed for the organisms with a large number of available protein structures including four eukaryotes, two bacteria and one archaeon. The distribution of the effects of mutations in the core on protein stability is universal and indistinguishable in eukaryotes and bacteria, centered at slightly destabilizing amino acid replacements, and with a heavy tail of more strongly destabilizing replacements. The distribution of mutational effects in the hyperthermophilic archaeon Thermococcus gammatolerans is significantly shifted toward strongly destabilizing replacements which is indicative of stronger constraints that are imposed on proteins in hyperthermophiles. The median effect of mutations is strongly, positively correlated with the relative core size, in evidence of the congruence between the two measures of protein robustness. However, both measures show only limited correlations to the expression level and selection pressure on protein-coding genes. Thus, the degree of robustness reflected in the universal distribution of mutational effects appears to be a fundamental, ancient feature of globular protein folds whereas the observed variations are largely neutral and uncoupled from short term protein evolution. A weak anticorrelation between protein core size and selection pressure is observed only for surface residues in prokaryotes but a stronger anticorrelation is observed for all residues in eukaryotic proteins. This substantial difference between proteins of prokaryotes and eukaryotes is likely to stem from the demonstrable higher compactness of prokaryotic proteins.

Selection maintaining protein stability at equilibrium

“…Current knowledge of protein folding can provide an exact formulation for the proportion of misfolded proteins as a function of folding free energy, and reasonable predictions (Schymkowitz et al, 2005;Yin et al, 2007;Tokuriki et al, 2007) of stability changes due to single amino acid substitutions in protein native structures. Thus, on the basis of knowledge of protein biophysics it became possible to study the effects of amino acid substitutions on protein stability and then the evolution of protein (Drummond and Wilke, 2008;Serohijos et al, 2012;Serohijos and Shakhnovich, 2014;Echave et al, 2015;Faure and Koonin, 2015).…”

Causes of evolutionary rate variation among protein sites

“…Also, while some studies are based on highly diverged data sets that include all major taxa 23;75 , others are based on a few closely related species 18 . Even though the mutational response of proteins of different major taxa seems to be universally distributed 136 , the extent to which patterns of rate variation among sites can be compared among different taxa has not been assessed. Thus, future work will have to test explicitly to what extent results obtained under one method, for one taxonomic group, or for one type of data carry over to very different methods, taxonomic groups, or data types.…”

Improved insights into protein thermal stability: from the molecular to the structurome scale

“…In the last decade, a series of investigations tackled this issue (e.g. [29][30][31][32][33][34] and references therein), but the answers remained elusive and too frequently model dependent. For example, it is still debated whether or not the distribution of the effects of amino acid substitutions on protein stability is universal and whether or not they are conserved during evolution.…”