CovaTide: Covalent Topology-Conditioned All-Atom Flow Matching For Linear and Cyclic Peptide Design

Peptides offer a versatile therapeutic modality for targeting protein surfaces, but conformational flexibility and susceptibility to proteolysis can limit their utility. Cyclization can mitigate these limitations, yet cyclic peptide design requires coordinating receptor-bound conformations with the local geometry of covalent closure. Existing methods often rely on post-generation filtering and endpoint mutation to obtain cyclic peptides, decoupling closure constraints from the generation of receptor-bound conformations. We present CovaTide, a receptor-conditioned all-atom flow model that jointly generates peptide sequences and structures under a prescribed covalent topology. CovaTide uses a deep topology adapter to repeatedly integrate residue-level connectivity and atom-level bond information, coupling global peptide conformations with local closure geometry throughout generation. This enables a single model to design linear peptides as well as head-to-tail, disulfide, and isopeptide cyclic peptides without post-generation endpoint mutation. To rank generated candidates, we further introduce a generation-aware confidence model that estimates peptide and interface errors. CovaTide outperforms the evaluated baselines in sequence and binding pose recovery for linear peptides and in cyclization, bond, and energy-based success rates for cyclic peptides. Together, these results support a unified formulation of linear and cyclic peptide binder design through multiscale covalent topology conditioning.