Abstract
Since the early days of molecular evolution, the conventional wisdom has been that the evolution of protein-coding genes is primarily determined by functional constraints. Yet recent evidence indicates that the evolution of these genes is strongly shaped by the biophysical processes of protein synthesis, protein folding, and specific as well as nonspecific protein-protein interactions. Selection pressures related to these biophysical processes affect primarily the amino-acid sequence of genes, but they also leave their mark on synonymous sites at the nucleotide level. While evidence for specific selection pressures related to protein biophysics is strong, there is currently no unifying framework that integrates the various selection pressures on coding sequences and disentangles their relative importance.