README.md

---
license: apache-2.0
tags:
- chemistry
- biology
---

<p align="center">
  <img src="assets/disco.png" alt="DISCO: Diffusion for Sequence-Structure Co-design" width="900"/>
</p>

<p align="center">
    <img src="assets/carbene.gif" width="700"/>
</p>

<p align="center">
  <a href="https://arxiv.org/abs/2604.05181"><img src="https://img.shields.io/badge/arXiv-94133F?style=for-the-badge&logo=arxiv" alt="arXiv"/></a>
  <a href="https://disco-design.github.io/"><img src="https://img.shields.io/badge/📝%20Blog-007A87?style=for-the-badge&logoColor=white" alt="Blog"/></a>
  <a href="https://github.com/DISCO-design/DISCO"><img src="https://img.shields.io/badge/GitHub-747474.svg?style=for-the-badge&logo=GitHub&logoColor=white" alt="HF"/></a>
</p>


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.