Geometric Deep Learning for Protein-Ligand Affinity Prediction with Hybrid Message Passing Strategies.

Abstract

Accurate prediction of protein-ligand affinity (PLA) is critical for drug discovery. Recent deep learning approaches have adopted data-driven models for PLA prediction by learning intrinsic patterns from one-dimensional (1D) sequential or two-dimensional (2D) graph representations of proteins and ligands. However, these low-dimensional methods overlook the three-dimensional (3D) geometric features, which are hypothesized to be critical in binding interaction. To address the above problem, we present a Geometric deep learning approach with Hybrid message passing strategies-HybridGeo, for protein-ligand affinity prediction. We adopt dual-view graph learning to model the intra- and inter-molecular atomic interactions and propose to aggregate the spatial information with hybrid strategies. In addition, to fully model the inter-residue dependency upon message aggregation, we adopt a geometric graph transformer on the residue-scale graph of protein pockets. Extensive experiments on the PDBbind dataset show that HybridGeo achieves state-of-the-art performance with a Root Mean Square Error (RMSE) of 1.172. HybridGeo also achieves the best among all baseline models on three external test sets, showcasing good generalizability and robustness. Through systematic ablation experiments, we validated the effectiveness of the proposed modules, and further demonstrated the superior performance of HybridGeo in predicting the binding affinity of macrocyclic compound complexes through case studies. Visualization analysis further indicates the biological interpretability of the model predictions. Our code is publicly available at https://github.com/anxiangbiye1231/HybridGeo.