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

TL;DR

This study clarifies how local packing density and longer-range effects influence protein sequence evolution, introducing a new local measure based on Voronoi cell volume that aligns with solvent accessibility in explaining evolutionary variability.

Contribution

The paper introduces a truly local measure of packing density using Voronoi cell volume, resolving previous disagreements and highlighting the combined influence of immediate and distant residues on evolution.

Findings

Voronoi cell volume correlates with solvent accessibility in explaining evolutionary rates.

Local and non-local effects together account for approximately 44% of variation in site-specific evolution.

Immediate neighbors and distant amino acids both significantly influence protein evolution.

Abstract

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 here that this discussion has been confounded by the definition of local packing density. The most commonly used measures of local packing, such as the contact number and the weighted contact number, represent by definition the combined effects of local packing density and longer-range effects. As an alternative, we here 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 both 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 action of the immediate amino-acid neighbors of that site and of effects mediated by more distant amino acids. We conclude that instead of contrasting solvent accessibility and local packing density, future research should emphasize the relative importance of immediate contacts and longer-range effects on evolutionary variation.