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| license: apache-2.0 |
| tags: |
| - chemistry |
| - biology |
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| <img src="assets/disco.png" alt="DISCO: Diffusion for Sequence-Structure Co-design" width="900"/> |
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| <img src="assets/carbene.gif" width="700"/> |
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| <a href="[https://arxiv.org/abs/2412.17762](https://arxiv.org/abs/XXXX.XXXXX)"><img src="https://img.shields.io/badge/arXiv-94133F?style=for-the-badge&logo=arxiv" alt="arXiv"/></a> |
| <a href="https://PLACEHOLDER_BLOG_URL"><img src="https://img.shields.io/badge/📝%20Blog-007A87?style=social&logoColor=white" alt="Jupyter"/></a> |
| <a href="https://huggingface.co/superdiff/"><img src="https://img.shields.io/badge/github-repo-blue?style=social&logo=github" alt="HF"/></a> |
| </p> |
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| 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. |
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| 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. |
