A Quantum Lens on Molecular Design: A Machine-Learned Energy Function from Interacting Quantum Atoms.

Abstract

Accurate predictions of the interactions (covalent bonds and non-covalent contacts between atoms) in a molecular system require scalable, accurate, and interpretable energy functions. While classical force fields and knowledge-based energy functions struggle to capture key electronic effects, quantum chemistry approaches such as density functional theory (DFT) provide the necessary accuracy but remain computationally demanding. Furthermore, gaining insight into interactions requires energy decomposition schemes. The Interacting Quantum Atoms (IQA) scheme is exceptionally attractive, offering a chemically intuitive, electron density (ED) topologically based separation into intra- and interatomic contributions, however its high computational cost remains a significant barrier for application to larger systems or tasks like ligand screening in drug discovery. We address these limitations by introducing a novel machine learning (ML) framework to predict accurate energies derived from the IQA scheme together with a comprehensive dataset of molecular systems and their calculated IQA decomposed energies. It enables the rapid and accurate prediction of DFT single point energies and dissects these energies in a physically meaningful and chemically intuitive manner. Our method predicts all intra-atomic energies and inter-atomic interaction energies (covalent and non-covalent) within a defined distance cutoff, providing an energy function that decomposes the total energy into specific atomic contributions. This advance makes the IQA method viable for analyzing interaction energies in applications previously inaccessible due to computational expense, such as elucidating ligand-binding mechanisms and informing rational drug design.