license: apache-2.0
tags:
- chemistry
- biology
DISCO (DIffusion for Sequence-structure CO-design) is a multimodal generative model that simultaneously co-designs protein sequences and 3D structures, conditioned on and co-folded with arbitrary biomolecules — including small-molecule ligands, DNA, and RNA. Unlike sequential pipelines that first generate a backbone and then apply inverse folding, DISCO generates both modalities jointly, enabling sequence-based objectives to inform structure generation and vice versa.
DISCO achieves state-of-the-art in silico performance in generating binders for diverse biomolecular targets with fine-grained property control. Applied to new-to-nature catalysis, DISCO was conditioned solely on reactive intermediates — without pre-specifying catalytic residues or relying on template scaffolds — to design diverse heme enzymes with novel active-site geometries. These enzymes catalyze new-to-nature carbene-transfer reactions, including alkene cyclopropanation, spirocyclopropanation, B–H and C(sp³)–H insertions, with top activities exceeding those of engineered enzymes. Random mutagenesis of a selected design further yielded a fourfold activity gain, indicating that the designed enzymes are evolvable.