Machine learning to predict de novo protein–protein interactions

Advances in machine learning for structural biology have dramatically enhanced our capacity to predict protein-protein interactions (PPIs). Here, we review recent developments in the computational prediction of PPIs, particularly focusing on innovations that enable interaction predictions that have no precedence in nature, termed de novo. We discuss novel machine learning algorithms for PPI prediction, including approaches based on co-folding and atomic graphs. We further highlight methods that learn from molecular surfaces, which can predict PPIs not found in nature including interactions induced by small molecules. Finally, we explore the emerging biotechnological applications enabled by these predictive capabilities, including the prediction of antibody-antigen complexes and molecular glue-induced PPIs, and discuss their potential to empower drug discovery and protein engineering.