A physics-aware neural network for protein–ligand interactions with quantum chemical accuracy

Abstract

Quantifying intermolecular interactions with quantum chemistry (QC) is useful for many chemical problems, including understanding the nature of protein–ligand interactions. Unfortunately, QC computations on protein–ligand systems are too computationally expensive for most use cases. The flourishing field of machine-learned (ML) potentials is a promising solution, but it is limited by an inability to easily capture long range, non-local interactions. In this work we develop an atomic-pairwise neural network (AP-Net) specialized for modeling intermolecular interactions. This model benefits from a number of physical constraints, including a two-component equivariant message passing neural network architecture that predicts interaction energies via an intermediate prediction of monomer electron densities. The AP-Net model is trained on a comprehensive dataset composed of paired ligand and protein fragments. This model accurately predicts QC-quality interaction energies of protein–ligand systems at a computational cost reduced by orders of magnitude. Applications of the AP-Net model to molecular crystal structure prediction are explored, as well as limitations in modeling highly polarizable systems.