Developing a Machine-Learning Interatomic Potential for Non-Covalent Interactions in Proteins

Abstract

Machine learning interatomic potentials (MLIPs) enable efficient modeling of molecular interactions with quantum mechanical (QM) accuracy. However, constructing robust and representative training datasets that capture subtle, system-specific interaction motifs remains challenging. We introduce PANIP (PAirwise Non-covalent Interaction Potential), an ensemble MLIP model built upon the NequIP framework and trained on non-covalent interactions (NCIs) between protein-derived fragments. PANIP is trained using an automated multi-fidelity active learning (MFAL) workflow, in which a representative training subset, termed PDB-FRAGID (PDB Fragment Interaction Dataset), was distilled from an otherwise prohibitively large pool of fragment dimers extracted from the Protein Data Bank (PDB). PANIP retains $\omega$B97X-D3BJ/def2-TZVPP-level accuracy and achieves mean absolute errors below 0.2 kcal/mol on out-of-distribution systems, demonstrating excellent transferability across diverse NCI motifs. Compared to the widely used ANI-2x potential, PANIP delivers substantially lower errors, particularly for charged and strongly interacting dimers. Coupled with a fragmentation-based energy decomposition scheme, PANIP estimates protein-ligand binding energies at near force-field computational cost yet QM-level accuracy, enabling its use as a fragment-based scoring function that rivals specialized docking scoring functions.