Selection on protein structure, interaction, and sequence

Characterizing the probabilities of observing amino acid substitutions at specific sites in a protein over evolutionary time is a major goal in the field of molecular evolution. While purely statistical approaches at different levels of complexity exist, approaches rooted in underlying biological processes are necessary to characterize both the context‐dependence of sequence changes (epistasis) and to extrapolate to sequences not observed in biological databases. To develop such approaches, an understanding of the different selective forces that act on amino acid substitution is necessary. Here, an overview of selection on and corresponding modeling of folding stability, folding specificity, binding affinity and specificity for ligands, the evolution of new binding sites on protein surfaces, protein dynamics, intrinsic disorder, and protein aggregation as well as the interplay with protein expression level (concentration) and biased mutational processes are presented.