Simultaneous identification of specifically interacting paralogs and interprotein contacts by direct coupling analysis

Most biological processes rely on specific interactions between proteins, but the experimental characterization of protein−protein interactions is a labor-intensive task of frequently uncertain outcome. Computational methods based on exponentially growing genomic databases are urgently needed. It has recently been shown that coevolutionary methods are able to detect correlated mutations between residues in different proteins, which are in contact across the interaction interface, thus enabling the structure prediction of protein complexes. Here we show that the applicability of coevolutionary methods is much broader, connecting multiple scales relevant in protein−protein interaction: the residue scale of interprotein contacts, the protein scale of specific interactions between paralogous proteins, and the evolutionary scale of conserved interactions between homologous protein families.