Predicting protein-protein interactions in the human proteome

Protein-protein interactions (PPIs) are essential for biological function. Coevolutionary analysis and deep-learning (DL)–based protein structure prediction have enabled comprehensive PPI identification in bacteria and yeast, but these approaches have had limited success for the more complex human proteome. We overcame this challenge by enhancing the coevolutionary signals with sevenfold-deeper multiple sequence alignments harvested from 30 petabytes of unassembled genomic data and developing a new DL network trained on augmented datasets of domain-domain interactions from 200 million predicted protein structures. We systematically screened 200 million human protein pairs and predicted 17,849 interactions with an expected precision of 90%, of which 3631 interactions were not identified in previous experimental screens. Three-dimensional models of these predicted interactions provide numerous hypotheses about protein function and mechanisms of human diseases.