Abstract
In protein evolution, due to functional and biophysical constraints, the rates of amino acid substitution differ from site to site. Among the best predictors of site-specific rates are solvent accessibility and packing density. The packing density measure that best correlates with rates is the weighted contact number (WCN), the sum of inverse square distances between a site’s Cα and the Cα of the other sites. According to a mechanistic stress model proposed recently, rates are determined by packing because mutating packed sites stresses and destabilizes the protein’s active conformation. While WCN is a measure of Cα packing, mutations replace side chains. Here, we consider whether a site’s evolutionary divergence is constrained by main-chain packing or side-chain packing. To address this issue, we extended the stress theory to model side chains explicitly. The theory predicts that rates should depend solely on side-chain contact density. We tested this prediction on a data set of structurally and functionally diverse monomeric enzymes. We compared side-chain contact density with main-chain contact density measures and with relative solvent accessibility (RSA). We found that side-chain contact density is the best predictor of rate variation among sites (it explains 39.2% of the variation). Moreover, the independent contribution of main-chain contact density measures and RSA are negligible. Thus, as predicted by the stress theory, site-specific evolutionary rates are determined by side-chain packing.
Highlights
Why do some protein sites evolve more slowly than others? Protein evolution is driven by random mutations and shaped by natural selection (Liberles et al, 2012; Sikosek & Chan, 2014)
Theory we show that the mechanistic stress model of protein evolution predicts that the substitution rate of a protein site is determined by the packing density of its side chain
We theoretically derived a new measure of contact density, the side-chain weighted contact number WCNαρρ which, according to the stress model, should be the sole structural determinant of site-specific evolutionary rates
Summary
Why do some protein sites evolve more slowly than others? Protein evolution is driven by random mutations and shaped by natural selection (Liberles et al, 2012; Sikosek & Chan, 2014). Mutations are selected depending on their impact on functional properties, such as the chemical nature of catalytic residues, active site conformation, and the protein’s ability to fold rapidly and stably. Since changes of these properties depend on the mutated site, amino acid substitution rates vary from site to site. The main structural predictor was believed to be solvent accessibility, as quantified by the Relative Solvent Accessibility (RSA) (Bustamante, Townsend & Hartl, 2000; Conant & Stadler, 2009; Franzosa & Xia, 2009; Ramsey et al, 2011; Shahmoradi et al, 2014). Local packing density, quantified by the Weighted Contact Number (WCN), predicts evolutionary rates at least as well as RSA (Shih & Hwang, 2012; Yeh et al, 2014a; Yeh et al, 2014b)
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