The Relationship Between Relative Solvent Accessibility and Evolutionary Rate in Protein Evolution

Abstract

Recent work with Saccharomyces cerevisiae shows a linear relationship between the evolutionary rate of sites and the relative solvent accessibility (RSA) of the corresponding residues in the folded protein. Here, we aim to develop a mathematical model that can reproduce this linear relationship. We first demonstrate that two models that both seem reasonable choices (a simple model in which selection strength correlates with RSA and a more complex model based on RSA-dependent amino acid distributions) fail to reproduce the observed relationship. We then develop a model on the basis of observed site-specific amino acid distributions and show that this model behaves appropriately. We conclude that evolutionary rates are directly linked to the distribution of amino acids at individual sites. Because of this link, any future insight into the biophysical mechanisms that determine amino acid distributions will improve our understanding of evolutionary rates.T HE requirement for successful and efficient protein folding imposes significant biophysical constraints on coding sequences. These constraints shape how sequences evolve. Mutations that interfere with correct folding will generally be removed by purifying selection. Likewise, mutations that do not interfere with folding are often neutral, or nearly so, and accumulate over time. As a consequence of this interaction between protein biophysics and molecular evolution, signatures of protein structure can be found in the divergence

Extensively Parameterized Mutation–Selection Models Reliably Capture Site-Specific Selective Constraint

“…We ensured that each simulation reflected evolutionary heterogeneity seen in real proteins by deriving simulation parameterizations from two different empirical data sources. The first simulation data set derived codon fitness parameters from site-specific amino acid frequencies in structurally curated natural amino-acid alignments (Ramsey et al 2011). We obtained site-specific fitness parameters for the second simulation data set using Mutation-Selection Model Performance .…”

“…First, we used a set of structurally curated natural amino-acid alignments, with each sequence homologous to a given PDB structure, compiled by Ramsey et al (2011). For each of those alignments that contained at least 150 taxa, we calculated each site's amino acid frequencies, which we converted to codon frequencies under the assumption that all synonymous codons for a given amino acid had the same frequency.…”

“…A growing body of research has demonstrated that these constraints lead individual protein sites to have distinct tolerances to different amino acids (Porto et al 2004;Ramsey et al 2011;Pollack et al 2012;Ashenberg et al 2013;Bloom 2014aBloom , 2014bRisso et al 2014;Abriata et al 2015;Doud et al 2015;Echave et al 2016). Recent experimental studies have further demonstrated that, for at least several proteins, site-wise amino-acid preferences are broadly conserved over evolutionary time (Ashenberg et al 2013;Risso et al 2014;Doud et al 2015).…”

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“…The yeast-proteins data set was taken from Ramsey et al (2011) and comprised 38 protein structures homologous to an open reading frame in Saccharomyces cerevisiae. For each of those structures, we had at least 50 homologous natural sequences, also taken from Ramsey et al (2011). The protein-domain data set was taken from Ollikainen and Kortemme (2013) and comprised 40 protein domains.…”

“…In particular, hydrophobic residues tend to be more frequent in the core and polar residues tend to be more frequent on the surface. Further, sites in the core of a protein tend to be more conserved and to evolve slower than surface sites (Mirny and Shakhnovich, 1999;Goldman et al, 1998;Bustamante et al, 2000;Conant and Stadler, 2009;Franzosa and Xia, 2009;Ramsey et al, 2011;Scherrer et al, 2012;Meyer and Wilke, 2012). Presumably, sites in the core tend to be conserved because mutations at these sites are more likely to destablize the protein fold, due to steric clashes (Chothia and Finkelstein, 1990).…”