Relationship between protein thermodynamic constraints and variation of evolutionary rates among sites

Echave, Julián; Jackson, Eleisha L.; Wilke, Claus O.

doi:10.1101/009423

Cited by 19 publications

(42 citation statements)

References 49 publications

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“…Taken together, these observations unexpectedly indicate that robustness of proteins to mutation inferred from the ΔΔG distribution obtained using FoldX is linked to abundance in bacteria but not in eukaryotes and is largely decoupled from sequence evolution in all tested organisms. As shown previously, the link between evolutionary rate and robustness could be stronger at the per-residue level than it is on the whole protein level [35, 55, 56]. …”

Section: Resultsmentioning

confidence: 94%

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

Faure

Koonin

2015

Phys. Biol.

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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.

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Section: Resultsmentioning

confidence: 94%

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

Faure

Koonin

2015

Phys. Biol.

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“…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).…”

Section: Discussionmentioning

confidence: 99%

“…Also, it was shown (Serohijos et al, 2013) that highly abundant proteins had to be more stable than low abundant ones. Relationship between evolutionary rate and protein stability is studied from various points of view (Echave et al, 2015;Faure and Koonin, 2015).…”

Section: Introductionmentioning

confidence: 99%

Selection maintaining protein stability at equilibrium

Miyazawa

2016

Journal of Theoretical Biology

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The common understanding of protein evolution has been that neutral mutations are fixed by random drift, and a proportion of neutral mutations depending on the strength of structural and functional constraints primarily determines evolutionary rate. Recently it was indicated that fitness costs due to misfolded proteins are a determinant of evolutionary rate and selection originating in protein stability is a driving force of protein evolution. Here we examine protein evolution under the selection maintaining protein stability.Protein fitness is a generic form of fitness costs due to misfolded proteins; s = κ exp(∆G/kT )(1 − exp(∆∆G/kT )), where s and ∆∆G are selective advantage and stability change of a mutant protein, ∆G is the folding free energy of the wild-type protein, and κ is a parameter representing protein abundance and indispensability. The distribution of ∆∆G is approximated to be a bi-Gaussian distribution, which represents structurally slightly-or highly-constrained sites. Also, the mean of the distribution is negatively proportional to ∆G.The evolution of this gene has an equilibrium point (∆G e ) of protein stability, the range of which is consistent with observed values in the ProTherm database. 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 lowabundant, non-essential proteins of ∆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 K a /K s is less than 1. Slow evolutionary rates can be caused by both high protein abundance/indispensability and large effective population size, which produces positive shifts of ∆∆G through decreasing ∆G e , and strong structural constraints, which directly make ∆∆G more positive. Protein abun- dance/indispensability more affect evolutionary rate for less constrained proteins, and structural constraint for less abundant, less essential proteins. The effect of protein indispensability on evolutionary rate may be hidden by the variation of protein abundance and detected only in low-abundant proteins. Also, protein stability (−∆G e /kT ) and K a /K s are predicted to decrease as growth temperature increases. Highlights• Protein stability is kept at equilibrium by random drift and positive selection.• Neutral selection is predominant only for low-abundant, non-essential proteins.• Protein abundance more decreases evolutionary rate for less-constrained proteins.• Structural constraint more decreases evolutionary rate for less-abundant, less-essential proteins.• Protein stability (−∆G e /kT ) and K a /K s are predicted to decrease as growth temperature increases.

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“…We analyzed the same data set of 209 monomeric enzymes we have previously analyzed and that was originally published with four additional proteins . The enzymes were originally randomly picked from the Catalytic Site Atlas 2.2.11, range from 95 to 1287 amino acids in length, and include representatives from all six main EC functional classes and domains of all main SCOP structural classes .…”

Section: Methodsmentioning

confidence: 99%

“…A variety of site‐specific structural characteristics have been proposed over the past decade to predict protein sequence evolution from structural properties. Among the most important and widely discussed are the Relative Solvent Accessibility (RSA), Contact Number (CN), measures of thermodynamic stability changes due to mutations at individual sites in proteins, protein designability, and measures of local flexibility, such as the B factor, or flexibility measures based on elastic network models and Molecular Dynamics (MD) simulations, or direct comparison of fluctuations among static structures of homologous proteins . (For a recent review, see Ref.…”

Section: Introductionmentioning

confidence: 99%

Dissecting the roles of local packing density and longer‐range effects in protein sequence evolution

Shahmoradi

Wilke

2016

Proteins

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What are the structural determinants of protein sequence evolution? A number of site-specific structural characteristics have been proposed, most of which are broadly related to either the density of contacts or the solvent accessibility of individual residues. Most importantly, there has been disagreement in the literature over the relative importance of solvent accessibility and local packing density for explaining site-specific sequence variability in proteins. We show that this discussion has been confounded by the definition of local packing density. The most commonly used measures of local packing, such as contact number and the weighted contact number, represent the combined effects of local packing density and longer-range effects. As an alternative, we propose a truly local measure of packing density around a single residue, based on the Voronoi cell volume. We show that the Voronoi cell volume, when calculated relative to the geometric center of amino-acid side chains, behaves nearly identically to the relative solvent accessibility, and each individually can explain, on average, approximately 34% of the site-specific variation in evolutionary rate in a data set of 209 enzymes. An additional 10% of variation can be explained by non-local effects that are captured in the weighted contact number. Consequently, evolutionary variation at a site is determined by the combined effects of the immediate amino-acid neighbors of that site and effects mediated by more distant amino acids. We conclude that instead of contrasting solvent accessibility and local packing density, future research should emphasize on the relative importance of immediate contacts and longer-range effects on evolutionary variation.

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Relationship between protein thermodynamic constraints and variation of evolutionary rates among sites

Cited by 19 publications

References 49 publications

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

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

Selection maintaining protein stability at equilibrium

Dissecting the roles of local packing density and longer‐range effects in protein sequence evolution

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