Site-Specific Structural Constraints on Protein Sequence Evolutionary Divergence: Local Packing Density versus Solvent Exposure

Protein sequences evolve under selection pressures imposed by functional and biophysical requirements, resulting in site-dependent rates of amino acid substitution. Relative solvent accessibility (RSA) and local packing density (LPD) have emerged as the best candidates to quantify structural constraint. Recent research assumes that RSA is the main determinantofsequencedivergence.However,it isnotyetclearwhichisthebestpredictorofsubstitutionrates. Toaddressthis issue, we compared RSA and LPD with site-specific rates of evolution for a diverse data set of enzymes. In contrast with recent studies, we found that LPD measures correlate better than RSA with evolutionary rate. Moreover, the independent contributionofRSAisminor.TakingintoaccountthatLPDisrelatedtobackboneflexibility,weputforwardthepossibility thattherateofevolutionofasiteisdeterminedbytheeasewithwhichthebackbonedeformstoaccommodatemutations.