Structure-based prediction of protein-protein interactions on a genome-wide scale

The genome-wide identification of pairs of interacting proteins is an important step in the elucidation of cell regulatory mechanisms(1,2). Much of our present knowledge derives from high-throughput techniques such as the yeast two-hybrid assay and affinity purification(3), as well as from manual curation of experiments on individual systems(4). A variety of computational approaches based, for example, on sequence homology, gene co-expression and phylogenetic profiles, have also been developed for the genome-wide inference of protein-protein interactions (PPIs)(5,6). Yet comparative studies suggest that the development of accurate and complete repertoires of PPIs is still in its early stages(7-9). Here we show that three-dimensional structural information can be used to predict PPIs with an accuracy and coverage that are superior to predictions based on non-structural evidence. Moreover, an algorithm, termed PrePPI, which combines structural information with other functional clues, is comparable in accuracy to high-throughput experiments, yielding over 30,000 high-confidence interactions for yeast and over 300,000 for human. Experimental tests of a number of predictions demonstrate the ability of the PrePPI algorithm to identify unexpected PPIs of considerable biological interest. The surprising effectiveness of three-dimensional structural information can be attributed to the use of homology models combined with the exploitation of both close and remote geometric relationships between proteins.