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Vilya-2 is a diffusion transformer that enhances the structural modeling of peptide therapeutics by extending the all-atom representation from its predecessor, Vilya-1, to include interactions with protein targets. This model achieves remarkable accuracy, recovering 59.1% of peptide interfaces to sub-2 脜 backbone RMSD, significantly outperforming existing co-folding models. Additionally, Vilya-2 demonstrates exceptional generalizability, effectively modeling diverse molecular conformations and serving as a foundation model for enriching active compounds in drug discovery campaigns.
Vilya-2 redefines peptide structural modeling, achieving unprecedented accuracy and generalizability that outstrips traditional methods.
Structure-prediction networks built on co-evolutionary statistics have transformed protein-based drug discovery, yet their accuracy does not extend to peptide therapeutics--an increasingly important modality defined by non-canonical residues, macrocyclization, and complex topologies. We introduce Vilya-2, a diffusion transformer that extends the all-atom representation of Vilya-1 from modeling individual molecules to modeling their interactions with protein targets. This all-atom representation enables transfer learning between different molecular types, and delivers highly accurate structural modeling of peptides across sizes, classes, and compositions bound to therapeutically relevant targets. By generating diverse structural ensembles and ranking them with calibrated confidence, Vilya-2 recovers 59.1% of peptide interfaces to sub-2 {\AA} backbone RMSD, far exceeding the performance of a representative co-folding model even when that model is given the bound receptor as a template. In addition, Vilya-2 is state-of-the-art at small-molecule docking, and generalizes to novel protein-small molecule complexes unlike those seen in training. It also generalizes to modeling molecular conformations of diverse macrocycles and disulfide-stapled miniproteins several-fold larger than any molecule seen in training. Finally, Vilya-2 can be used as a foundation model, and fine-tuned to enrich for active compounds in hit-to-lead campaigns. By unifying predictive accuracy with broad generalizability across chemical space, Vilya-2 is the structure-prediction oracle that de novo peptide design pipelines require--establishing the all-atom approach as a general foundation for the design and evaluation of de novo peptide therapeutics.
