General Multimodal Protein Design Enables DNA-Encoding of Chemistry
Evolution is an extraordinary engine for enzymatic diversity, yet the chemistry it has explored remains a narrow slice of what DNA can encode. Deep generative models can design new proteins that bind ligands, but none have created enzymes without pre-specifying catalytic residues. We introduce DISCO (DIffusion for Sequence-structure CO-design), a multimodal model that co-designs protein sequence and 3D structure around arbitrary biomolecules, as well as inference-time scaling methods that optimize objectives across both modalities. Conditioned solely on reactive intermediates, DISCO designs 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(sp^3)-H insertions, with high activities exceeding those of engineered enzymes. Random mutagenesis of a selected design further confirmed that enzyme activity can be improved through directed evolution. By providing a scalable route to evolvable enzymes, DISCO broadens the potential scope of genetically encodable transformations. Code is available at https://github.com/DISCO-design/DISCO.
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Jarrid Rector-Brooks
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2026-04-08T07:43:10.581Z
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Jarrid Rector-Brooks
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Théophile Lambert
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Theophile Lambert
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Marta Skreta
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Marta Skreta
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Daniel Roth
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Yueming Long
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Zi-Qi Li
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Xi Zhang
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Miruna Cretu
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Tanvi Ganapathy
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Emily Jin
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Jason Yang
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Kirill Neklyudov
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Kirill Neklyudov
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Yoshua Bengio
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Alexander Tong
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2026-04-08T16:34:11.261Z
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Alexander Tong
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Frances H. Arnold
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Cheng-Hao Liu
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2026-04-09T08:07:12.207Z
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Chenghao Liu
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General Multimodal Protein Design Enables DNA-Encoding of Chemistry
Evolution is an extraordinary engine for enzymatic diversity, yet the chemistry it has explored remains a narrow slice of what DNA can encode. Deep generative models can design new proteins that bind ligands, but none have created enzymes without pre-specifying catalytic residues. We introduce DISCO (DIffusion for Sequence-structure CO-design), a multimodal model that co-designs protein sequence and 3D structure around arbitrary biomolecules, as well as inference-time scaling methods that optimize objectives across both modalities. Conditioned solely on reactive intermediates, DISCO designs 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(sp^3)-H insertions, with high activities exceeding those of engineered enzymes. Random mutagenesis of a selected design further confirmed that enzyme activity can be improved through directed evolution. By providing a scalable route to evolvable enzymes, DISCO broadens the potential scope of genetically encodable transformations. Code is available at https://github.com/DISCO-design/DISCO.
DISCO is a multimodal deep generative model that co-designs protein sequences and 3D structures to create novel heme enzymes with unprecedented catalytic capabilities.
deep generative models protein sequence design 3D structure prediction multimodal model reactive intermediates heme enzymes carbene-transfer reactions directed evolution enzyme catalysis