Accurate and generalizable protein-ligand binding affinity prediction with geometric deep learning

Abstract: Protein-ligand binding complexes are ubiquitous and essential to life. Protein-ligand binding affinity prediction (PLA) quantifies the binding strength between ligands and proteins, providing crucial insights for discovering and designing potential candidate ligands. While recent advances have been made in predicting protein-ligand complex structures, existing algorithms for interaction and affinity prediction suffer from a sharp decline in performance when handling ligands bound with novel unseen proteins. We propose IPBind, a geometric deep learning-based computational method, enabling robust predictions by leveraging interatomic potential between complex's bound and unbound status. Experimental results on widely used binding affinity prediction benchmarks demonstrate the effectiveness and universality of IPBind. Meanwhile, it provides atom-level insights into prediction. This work highlights the advantage of leveraging machine learning interatomic potential for predicting protein-ligand binding affinity.