Human protein interactome structure prediction at scale with Boltz-2

ABSTRACT In humans, protein-protein interactions mediate numerous biological processes and are central to both normal physiology and disease. While extensive research efforts have aimed to characterize the human protein interactome, atom-scale structural coverage is limited and remains challenging to resolve through experimental methodology alone. Boltz-2, a recent artificial intelligence/machine learning (AI/ML)-based model capable of interaction structure prediction, may serve this experimentally constrained objective. Here, we present de novo computed models of binary human protein interaction structures predicted using Boltz-2 based on biochemically determined interaction data sourced from the IntAct database. We assessed the predicted interaction structures through different confidence metrics, examined annotated protein domains with putative interaction involvement, and uncovered interaction networks within the context of biological processes and cancer, highlighting extensive interaction involvement of E3 ubiquitin-protein ligase Mdm2 and p53, among other proteins. This work demonstrates the utility of Boltz-2 for structural modeling of the human protein interactome while also providing novel functional and disease contextualization, holding broad significance for biomedical research at large. GRAPHICAL ABSTRACT Competing Interest Statement A.M.I. is a founder and partner of North Horizon, which is engaged in the development of artificial intelligence-based software. R.P. and W.A. are founders and equity shareholders of PhageNova Bio. R.P. is Chief Scientific Officer and a paid consultant of PhageNova Bio. R.P. and W.A are founders and equity shareholders of MBrace Therapeutics. R.P. and W.A. serve as paid consultants for MBrace Therapeutics. R.P. and W.A. have Sponsored Research Agreements (SRAs) in place with PhageNova Bio, MBrace Therapeutics, and Alnylam Pharmaceuticals; this study falls outside of the scope of these SRAs. These arrangements are managed in accordance with the established institutional conflict-of-interest policies of Rutgers, The State University of New Jersey. C.M. and S.K.B. declare no competing interests. Footnotes ↵‡ These authors jointly supervised the work. The manuscript was updated to include additional analyses within the Results section. Corresponding figure edits and additional supplementary data were included. Additional discussion points and references were also included. The title and abstract have also been revised.