Emergent Biological Capabilities in a Foundation Model for Molecular Interactions

원문 초록

Foundation models trained on large unlabeled corpora develop emergent capabilities, tasks that go beyond the training objective. We extend this paradigm to multimodal biology with Bonbon, a foundation model for molecular interactions trained on approximately 3.2 trillion tokens of paired protein-ligand sequences. From a single representation space, Bonbon exhibits three zero-shot emergent capabilities at hierarchical levels of resolution: functional (mechanism of action), residue (binding site localization, including orthosteric/allosteric discrimination), and bond (covalent versus non-covalent engagement). All three capabilities generalize to out-of-distribution complexes. Bonbon was trained on protein-ligand sequences alone, without any task-specific supervision and without structural coordinates. We conducted controlled scaling experiments across six model scales from 42M to 1.6B parameters; every capability evaluated shows a sharp jump at the largest scale on continuous metrics, even as pretraining loss decreases smoothly. This demonstrates that loss-based scaling laws alone are insufficient to predict when zero-shot emergent capabilities become available. The capabilities reported here emerge after training at a 1:2,000 parameter-to-token ratio to accommodate the sparsity of paired biological interaction data. The same frozen representations achieve state-of-the-art binding and affinity prediction at five orders of magnitude greater speed than co-folding methods. In prospective wet-lab validation across nine disease targets spanning seven protein families, Bonbon achieves a 61.5% dose-response hit rate on de novo compounds, yielding structurally novel molecules not previously reported to inhibit these proteins, including for out-of-distribution targets.