Recent work with Saccharomyces cerevisiae shows a linear relationship between the evolutionary rate of sites and the relative solvent accessibility (RSA) of the corresponding residues in the folded protein. Here, we aim to develop a mathematical model that can reproduce this linear relationship. We first demonstrate that two models that both seem reasonable choices (a simple model in which selection strength correlates with RSA and a more complex model based on RSA-dependent amino acid distributions) fail to reproduce the observed relationship. We then develop a model on the basis of observed site-specific amino acid distributions and show that this model behaves appropriately. We conclude that evolutionary rates are directly linked to the distribution of amino acids at individual sites. Because of this link, any future insight into the biophysical mechanisms that determine amino acid distributions will improve our understanding of evolutionary rates.T HE requirement for successful and efficient protein folding imposes significant biophysical constraints on coding sequences. These constraints shape how sequences evolve. Mutations that interfere with correct folding will generally be removed by purifying selection. Likewise, mutations that do not interfere with folding are often neutral, or nearly so, and accumulate over time. As a consequence of this interaction between protein biophysics and molecular evolution, signatures of protein structure can be found in the divergence

Economic Level IV. See Instructions for Authors for a complete description of levels of evidence.