DC-Flow: Target-Conditioned Cyclic Peptide Design via Delayed-Coupling Flow Matching

Target-conditioned cyclic peptide design requires coordinating interfacial side chains with macrocyclic closure. Existing end-to-end generators concurrently update geometric and chemical variables from noise, assigning residues to disordered coordinates. Meanwhile, predictor-assisted workflows often get stuck in local traps because they lack feedback in the propose-and-filter stage and ignore 3D structural proposals during sequence search. To overcome the drawbacks of these two paradigms, we propose DC-FLOW, a staged generative framework built around Delayed-Coupling Flow Matching. In principle, DC-FLOW postpones sequence and side-chain activation until a target-conditioned backbone takes shape, resolving structural ambiguity before chemical assignment. Then, it feeds delayed activations back into the backbone, achieving co-evolution of backbone geometry and emerging residue identities by coupling their flows. This mechanism enables more reliable macrocyclic closure and favorable interface packing. For predictor-assisted workflows, DC-FLOW supplies 3D proposals with in-trajectory guidance, enabling cascaded test-time scaling to prune redundant backbones and terminate unpromising refinement early. Extensive experiments show that DC-FLOW improves cyclization fidelity, diversity, and interface energetics, substantially increasing the yield of confident cyclic peptide binders under a fixed final-candidate budget. Our code is available at https://github.com/mianqiu00/DCFlow.