Starkly Speaking: General Multimodal Protein Design Enables DNA-Encoding of Chemistry

[Hannes Stärk]

Hi together,

Tomorrow we will talk about:


Speaker: Jarrid Rector-Brooks and Cheng-Hao Liu.

Jarrid Rector-Brooks is a PhD student at Mila and Université de Montréal advised by Yoshua Bengio, currently visiting Frances Arnold's lab at Caltech. His research focuses on computationally efficient generative modeling, the sampling problem, and generative models for the de novo design of molecular structures, with extensive work on protein generative models.

Cheng-Hao Liu is a postdoctoral fellow at Caltech with Frances Arnold. He did his PhD with Dmytro Perepichka at McGill University and Yoshua Bengio at Mila, and works across chemistry and machine learning on the design of molecules and materials with new physical properties.


Paper:
General Multimodal Protein Design Enables DNA-Encoding of Chemistry https://arxiv.org/abs/2604.05181 (Jarrid Rector-Brooks, Théophile Lambert, Marta Skreta, Daniel Roth, Yueming Long, Zi-Qi Li, Xi Zhang, Miruna Cretu, Francesca-Zhoufan Li, Tanvi Ganapathy, Emily Jin, Avishek Joey Bose, Jason Yang, Kirill Neklyudov, Yoshua Bengio, Alexander Tong, Frances H. Arnold, Cheng-Hao Liu)
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(sp3)-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.


Meeting Details:
Every Monday at 9:00 PT / 12:00 ET  /  18:00 CE(S)T
https://zoom.us/j/5775722530?pwd=ZzlGTXlDNThhUDZOdU4vN2JRMm5pQT09


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Hannes Stärk
Website: https://hannes-stark.com
PhD student at MIT