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

Understanding protein−protein interactions is central to our under- standing of almost all complex biological processes. Computational tools exploiting rapidly growing genomic databases to characterize protein−protein interactions are urgently needed. Such methods should connect multiple scales from evolutionary conserved interac- tions between families of homologous proteins, over the identifica- tion of specifically interacting proteins in the case of multiple paralogs inside a species, down to the prediction of residues being in physical contact across interaction interfaces. Statistical inference methods detecting residue−residue coevolution have recently trig- gered considerable progress in using sequence data for quaternary protein structure prediction; they require, however, large joint align- ments of homologous protein pairs known to interact. The genera- tion of such alignments is a complex computational task on its own; application of coevolutionary modeling has, in turn, been restricted to proteins without paralogs, or to bacterial systems with the corre- sponding coding genes being colocalized in operons. Here we show that the direct coupling analysis of residue coevolution can be ex- tended to connect the different scales, and simultaneously to match interacting paralogs, to identify interprotein residue−residue con- tacts and to discriminate interacting from noninteracting families in a multiprotein system. Our results extend the potential applications of coevolutionary analysis far beyond cases treatable so far.