EvoDiff is a general-purpose diffusion framework that combines evolutionary-scale data with the distinct conditioning capabilities of diffusion models for controllable protein generation in sequence space. EvoDiff generates high-fidelity, diverse, and structurally-plausible proteins that cover natural sequence and functional space.

Critically, EvoDiff can generate proteins inaccessible to structure-based models, such as those with disordered regions, while maintaining the ability to design scaffolds for functional structural motifs, demonstrating the universality of our sequence-based formulation.

EvoDiff will expand capabilities in protein engineering beyond the structure-function paradigm toward programmable, sequence-first design. The sequence and MSA models – EvoDiff-Seq and EvoDiff-MSA, respectively – were evaluated across a range of generation tasks to demonstrate their power for controllable protein design.