Signatures of coevolution in protein superfamilies

Protein superfamilies, such as G protein-coupled receptors, consist of a large number of evolutionarily related proteins. A multiple sequence alignment (MSA) from such a superfamily can help identify signatures of evolution. A way to detect amino acid residues (AAs) that are important for the structure and/or function of proteins is to identify a cohort of AAs that evolve in tandem to compensate for mutations at any of those positions. To characterize such coevolutionary patterns, a MSA of homologous sequences was used to identify pairs of AA positions from the alignment having statistically significant mutual information (MI). Pairs of such MSA positions that had high MI were represented as a graph to show multiple associations. In that graph, the MSA positions represented vertices whose edges were linked if position pairs had high MI. The vertices with high degree were validated to be evolutionarily correlated positions that were important for structure and/or function. Using subsets of more recently evolved proteins from the diverse superfamily, most of those positions were determined to be under purifying selection. This comparative genomic analysis may help infer protein structure and coevolution in protein-protein interactions.