Phylogenetic correlations can suffice to infer protein partners from sequences

Determining which proteins interact together is crucial to a systems-level understanding of the cell. Recently, algorithms based on Direct Coupling Analysis (DCA) pairwise maximum-entropy models have allowed to identify interaction partners among paralogous proteins from sequence data. This success of DCA at predicting protein-protein interactions could be mainly based on its known ability to identify pairs of residues that are in contact in the three-dimensional structure of protein complexes and that coevolve to remain physicochemically complementary. However, interacting proteins possess similar evolutionary histories. What is the role of purely phylogenetic correlations in the performance of DCA-based methods to infer interaction partners? To address this question, we employ controlled synthetic data that only involve phylogeny and no interactions or contacts. We find that DCA accurately identifies the pairs of synthetic sequences that share evolutionary history. While phylogenetic correlations confound the identification of contacting residues by DCA, they are thus useful to predict interacting partners among paralogs. We find that DCA performs as well as phylogenetic methods to this end, and slightly better than them with large and accurate training sets. Employing DCA or phylogenetic methods within an Iterative Pairing Algorithm (IPA) allows to predict pairs of evolutionary partners without a training set. We further demonstrate the ability of these various methods to correctly predict pairings among real paralogous proteins with genome proximity but no known direct physical interaction, illustrating the importance of phylogenetic correlations in natural data. However, for physically interacting and strongly coevolving proteins, DCA and mutual information outperform phylogenetic methods. We finally discuss how to distinguish physically interacting proteins from proteins that only share a common evolutionary history.Author summary: Many biologically important protein-protein interactions are conserved over evolutionary time scales. This leads to two different signals that can be used to computationally predict interactions between protein families and to identify specific interaction partners. First, the shared evolutionary history leads to highly similar phylogenetic relationships between interacting proteins of the two families. Second, the need to keep the interaction surfaces of partner proteins biophysically compatible causes a correlated amino-acid usage of interface residues. Employing simulated data, we show that the shared history alone can be used to detect partner proteins. Similar accuracies are achieved by algorithms comparing phylogenetic relationships and by methods based on Direct Coupling Analysis (DCA), which are primarily known for their ability to detect the second type of signal. Using natural sequence data, we show that in cases with shared evolutionary history but without known physical interactions, both methods work with similar accuracy, while for some physically interacting systems, DCA and mutual information outperform phylogenetic methods. We propose methods allowing both to predict interactions between protein families and to find interacting partners among paralogs.