# General Multimodal Protein Design Enables DNA-Encoding of Chemistry

arXiv: https://arxiv.org/abs/2604.05181 · HTML: https://mlsanity.com/paper/2604.05181/

## Key facts

- Cited by 4 papers in the map (data through 14 Oct 2026).
- Builds on 3 of its 58 references that are in the map.
- First posted on arXiv 6 Apr 2026.

## Builds on (most cited first, 3 of 3)

- [Path Planning for Masked Diffusion Model Sampling](https://mlsanity.com/paper/2502.03540/) (2025)
- [La-Proteina: Atomistic Protein Generation via Partially Latent Flow Matching](https://mlsanity.com/paper/2507.09466/) (2025)
- [Discrete Feynman-Kac Correctors](https://mlsanity.com/paper/2601.10403/) (2026)

## Built on by (most cited first, 4 of 4)

- [Strong Stochastic Flow Maps](https://mlsanity.com/paper/2606.01086/) (2026)
- [Active Flow Expansion for Out-of-Distribution Discovery: from Theory to Molecules](https://mlsanity.com/paper/2606.08802/) (2026)
- [Few-step Cofolding with All-Atom Flow Maps](https://mlsanity.com/paper/2606.08375/) (2026)
- [CODesign: Consistency from Data to Trajectory in All-Atom Protein Binder Co-Design](https://mlsanity.com/paper/2610.01773/) (2026)

## Abstract (arXiv)

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.