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Understanding protein-protein interactions is central to our understanding ofalmost all complex biological processes. Computational tools exploiting rapidlygrowing genomic databases to characterize protein-protein interactions areurgently needed. Such methods should connect multiple scales from evolutionaryconserved interactions between families of homologous proteins, over theidentification of specifically interacting proteins in the case of multipleparalogs inside a species, down to the prediction of residues being in physicalcontact across interaction interfaces. Statistical inference methods detectingresidue-residue coevolution have recently triggered considerable progress inusing sequence data for quaternary protein structure prediction; they require,however, large joint alignments of homologous protein pairs known to interact.The generation of such alignments is a complex computational task on its own;application of coevolutionary modeling has in turn been restricted to proteinswithout paralogs, or to bacterial systems with the corresponding coding genesbeing co-localized in operons. Here we show that the Direct-Coupling Analysisof residue coevolution can be extended to connect the different scales, andsimultaneously to match interacting paralogs, to identify inter-proteinresidue-residue contacts and to discriminate interacting from noninteractingfamilies in a multiprotein system. Our results extend the potentialapplications of coevolutionary analysis far beyond cases treatable so far.

Simultaneous identification of specifically interacting paralogs and inter-protein contacts by Direct-Coupling Analysis