What happened
The historical dichotomy between small-molecule pocket and extended protein interfaces misrepresents the physical reality of peptide recognition.1,2 Here we show that peptide binding is not a simple structural intermediate but a distinctly multimodal landscape comprising small-molecule-like pockets, protein-like interfaces, and a previously unrecognized third mode. This third regime is governed by a hierarchical subpocket architecture where a flattened surface achieves near-complete peptide engagement through spatially partitioned hydrophobic components. To maintain stability, an incompletely enclosed dominant anchor cooperates with highly hydrated auxiliary subpockets and an asymmetric receptor coupling mechanism that concentrates energy in an adjacent continuous water network. Because this unique binding mode suffers from extreme data scarcity, standard deep learning models fail to capture its physics.3,4 To resolve this, we mapped these specific geometric signatures to mine structurally faithful training distributions from global protein interactomes. Based on these data, we trained Ourotide, a deep learning framework coupling conditional geometric flow matching with interface-aware affinity learning. Evaluated across peptides up to 65 residues, Ourotide outperforms generalist models in backbone accuracy, interface recovery, and affinity prediction. This approach suggests that overcoming data scarcity in the physical sciences requires physics-guided data augmentation rather than naive statistical scaling.