Protein binding and folding through an evolutionary lens

Protein-protein associations are often mediated by an intrinsically disordered protein region interacting with a folded domain in a coupled binding and folding reaction. Classic physical organic chemistry approaches together with structural biology have shed light on mechanistic aspects of such reactions. Further insight into general principles may be obtained by interpreting the results through an evolutionary lens. This review attempts to provide an overview on how the analysis of binding and folding reactions can benefit from an evolutionary approach, and is aimed at protein scientists without a background in evolution. Evolution constantly reshapes existing proteins by sampling more or less fit variants. Most new variants are weeded out as generations and new species come and go over hundreds to hundreds of millions of years. The huge ongoing genome sequencing efforts have provided us with a snapshot of existing adapted fit-for-purpose protein homologs in thousands of different organisms. Comparison of present-day orthologs and paralogs highlights general principles of the evolution of coupled binding and folding reactions and demonstrate a great potential for evolution to operate on disordered regions and modulate affinity and specificity of the interactions.