High-throughput experiments in bacteria and eukaryotic cells have identified tens of thousands of possible interactions between proteins. This genome-wide view of the protein interaction universe is coarse-grained, whilst fine-grained detail of macro-molecular interactions critically depends on lower throughput, labor-intensive experiments. Computational approaches using measures of residue co-evolution across proteins show promise, but have been limited to specific interactions. Here we present a new generalized method showing that patterns of evolutionary sequence changes across proteins reflect residues that are close in space, and with sufficient accuracy to determine the three-dimensional structure of the protein complexes. We demonstrate that the inferred evolutionary coupling scores  distinguish between interacting and non-interacting proteins and the accurate prediction of residue interactions . To illustrate the utility of the method, we predict  unknown 3D interactions between subunits of ATP synthase and find results consistent with detailed experimental data. We expect that the method can be generalized to genome-wide interaction predictions at residue resolution.
High-throughput experiments in bacteria and eukaryotic cells have identified tens of thousands of interactions between proteins. This genome-wide view of the protein interaction universe is coarse-grained, whilst fine-grained detail of macro-molecular interactions critically depends on lower throughput, labor-intensive experiments. Computational approaches using measures of residue co-evolution across proteins show promise, but have been limited to specific interactions. Here we present a new generalized method showing that patterns of evolutionary sequence changes across proteins reflect residues that are close in space, with sufficient accuracy to determine the three-dimensional structure of the protein complexes. We demonstrate that the inferred evolutionary coupling scores accurately predict inter-protein residue interactions and can distinguish between interacting and non-interacting proteins . To illustrate the utility of the method, we predict co-evolved contacts between 50 E. coli complexes (of unknown structure), including the unknown 3D interactions between subunits of ATP synthase and find results consistent with detailed experimental data. We expect that the method can be generalized to genome-wide interaction predictions at residue resolution.
D
possible
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and
A
accurately predict inter-protein residue interactions and can
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and the accurate prediction of residue interactions
A
co-evolved contacts between 50 E. coli complexes (of unknown structure), including the