Maximum allowed solvent accessibilites of residues in proteins

TL;DR

This paper introduces a new normalization scale for solvent accessibility in proteins, providing tighter upper bounds on ASA values, which improves the accuracy of RSA calculations and enhances hydrophobicity scale correlations.

Contribution

The authors derive a novel normalization scale for ASA that better reflects empirical data, correcting previous underestimations and enabling more accurate biophysical and evolutionary analyses.

Findings

New normalization scale exceeds previous values by up to 20%

Empirically derived hydrophobicity scales show increased correlation with experimental data

Both empirical analysis and systematic enumeration support the new bounds

Abstract

The relative solvent accessibility (RSA) of a residue in a protein measures the extent of burial or exposure of that residue in the 3D structure. RSA is frequently used to describe a protein's biophysical or evolutionary properties. To calculate RSA, a residue's solvent accessibility (ASA) needs to be normalized by a suitable reference value for the given amino acid; several normalization scales have previously been proposed. However, these scales do not provide tight upper bounds on ASA values frequently observed in empirical crystal structures. Instead, they underestimate the largest allowed ASA values, by up to 20%. As a result, many empirical crystal structures contain residues that seem to have RSA values in excess of one. Here, we derive a new normalization scale that does provide a tight upper bound on observed ASA values. We pursue two complementary strategies, one based on extensive analysis of empirical structures and one based on systematic enumeration of biophysically allowed tripeptides. Both approaches yield congruent results that consistently exceed published values. We conclude that previously published ASA normalization values were too small, primarily because the conformations that maximize ASA had not been correctly identified. As an application of our results, we show that empirically derived hydrophobicity scales are sensitive to accurate RSA calculation, and we derive new hydrophobicity scales that show increased correlation with experimentally measured scales.