PepRIG: Receptor-Guided Sequence–Structure Coupling for All-Atom Peptide Generation

Peptides have diverse biological activities that support applications in targeted therapy, functional foods, and nutritional health. These activities depend on molecular interactions shaped by peptide sequence and structure, making their joint design important for developing peptides with desired functions. Generative models support joint peptide sequence–structure design, yet receptor compatibility requires residue identities and spatial arrangements to jointly establish complementary interactions at the binding interface. The central challenge is to coordinate these interdependent choices throughout generation, so that sequence and structure adapt together to the target receptor. To address this challenge, we introduce PepRIG, a receptor-guided all-atom diffusion framework that couples sequence and structure generation at the representation and potential levels. Specifically, Interface-Guided Co-Adaptation (IGCA) integrates multiscale receptor-interface information into shared representations, guiding sequence and structure updates with a common description of peptide–receptor interactions. Complementing this shared representation, Reciprocal Binding Potential (RBP) derives coupled gradients from a receptor-conditioned scalar potential, allowing each modality's correction to account for the other modality. Extensive experiments on LNR and PepBDB demonstrate that PepRIG outperforms strong baselines on key evaluation criteria, achieving state-of-the-art results across both benchmarks. Ablation studies demonstrate the complementary benefits of the two mechanisms, supporting shared receptor guidance for coupled sequence–structure generation.