Maximum Allowed Solvent Accessibilites of Residues in Proteins

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.

Temperature dependence of amino acid hydrophobicities

“…2C) exceeded that expected for an additional random predictor, we obtained P < 0.0001 for each of the two transfer free energies and P = 0.02 for their interaction. Using the results of a more recent model for predicting ASA fold , proposed by Tien et al (32), similar values of the three coefficients were obtained (SI Appendix, Table S2). …”

“…Considerable effort has been devoted to the search for a general scale that might relate the physical properties of the side-chain of each the 20 amino acids to its solvent-accessible surface area in folded proteins (ASA fold ), as determined using a probe that is often a water-sized sphere (24)(25)(26)(27)(28)(29)(30)(31)(32). Values of ASA fold depend on the size and shape of the probe, the presence or absence of steric constraints on the approach of a probe that may be imposed by flanking peptide bonds, and the rotameric preferences of the larger side-chains, all of which can affect the normalization of estimated ASA values.…”

Genome of the pitcher plant Cephalotus reveals genetic changes associated with carnivory

“…Predicted models were visualized using UCSF Chimera 1.10 102 . Relative exposure of amino acid surfaces was calculated by dividing solvent-accessible surface in protein structures by the theoretical maximum of corresponding amino acids in Gly-X-Gly tripeptide contexts 103 . The relative solvent-accessible surface area for a paired amino acid substitution was reported by averaging values in proteins constituting the two clades ( Supplementary Fig.…”

Computational prediction of the tolerance to amino-acid deletion in green-fluorescent protein

“…Furthermore, indel events may be 14 more likely to occur on the protein surface, where residues are more exposed to solvent, 15 rather than in a protein's core [13,14]. Thus, constraints on indel events appear to 16 mirror those on substitution events, in that amino-acid substitutions are most frequent 17 in unstructured regions and on the protein surface [1]. In spite of these observations, 18 however, the fundamental structural properties which govern whether indel events are 19 tolerated remain largely uncharacterized, ultimately hindering a complete 20 understanding of how protein structure influences protein evolution.…”

“…Specifically, we consider relative solvent accessibility (RSA) and 31 weighted contact number (WCN). RSA, which ranges from 0 to 1 [17], measures how 32 exposed a given residue is to solvent, with 0 representing a fully buried residue and 1 33 representing a fully exposed residue. WCN is a measure of packing density [18].…”