UniPocket: Physics-Aware Geometric Graph Learning with Manifold Completeness for Ligand-Specific Binding Site Prediction

摘要

Predicting ligand binding sites on protein surfaces requires capturing complex local geometries and satisfying physical constraints. Existing voxel-based methods suffer from high computational costs and rotation sensitivity, while standard point-cloud GNNs often lack geometric completeness—failing to distinguish chiral structures or subtle topological variations. In this work, we propose UniPocket, a novel E(3)-equivariant surface graph neural network. Inspired by recent advances in efficient geometric completeness, UniPocket constructs a Manifold-Aware Surface Encoder that utilizes local surface normals as virtual reference frames to capture complete geometric invariants without expensive high-order tensor products. Furthermore, we introduce a Ligand-Gated Message Passing mechanism to condition the surface features on the chemical semantics of the target ligand, and a Physics-Aware Vector Rejection Module that enforces steric constraints via orthogonal vector decomposition. Experimental results on standard benchmarks (PDBbind, COACH420, Holo4k) demonstrate that UniPocket achieves state-of-the-art performance, validating that geometric completeness and physical inductive biases are key to precise binding site detection.