  Protein-protein interactions are fundamental to many biological processes.
Experimental screens have identified tens of thousands of interactions and
structural biology has provided detailed functional insight for select 3D
protein complexes. An alternative rich source of information about protein
interactions is the evolutionary sequence record. Building on earlier work, we
show that analysis of correlated evolutionary sequence changes across proteins
identifies residues that are close in space with sufficient accuracy to
determine the three-dimensional structure of the protein complexes. We evaluate
prediction performance in blinded tests on 76 complexes of known 3D structure,
predict protein-protein contacts in 32 complexes of unknown structure, and
demonstrate how evolutionary couplings can be used to distinguish between
interacting and non-interacting protein pairs in a large complex. With the
current growth of sequence databases, we expect that the method can be
generalized to genome-wide elucidation of protein-protein interaction networks
and used for interaction predictions at residue resolution.
