Development of Range-Corrected Deep Learning Potentials for Fast, Accurate Quantum Mechanical/Molecular Mechanical Simulations of Chemical Reactions in Solution

• Published in: Journal of chemical theory and computation 2021-11, Vol.17 (11), p.6993-7009
• Main Authors: Zeng, Jinzhe, Giese, Timothy J, Ekesan, Şölen, York, Darrin M
• Format: Article
• Language: English
• Subjects: Chemical reactions; Deep learning; Electrostatics; Energy; Free energy; High temperature; Machine learning; Model testing; Neural networks; Quantum mechanics; Reaction Mechanisms; Simulation; Training; Two dimensional models
• ISSN: 1549-9618; 1549-9626
• DOI: 10.1021/acs.jctc.1c00201

We develop a new deep potentialrange correction (DPRc) machine learning potential for combined quantum mechanical/molecular mechanical (QM/MM) simulations of chemical reactions in the condensed phase. The new range correction enables short-ranged QM/MM interactions to be tuned for higher accuracy, and the correction smoothly vanishes within a specified cutoff. We further develop an active learning procedure for robust neural network training. We test the DPRc model and training procedure against a series of six nonenzymatic phosphoryl transfer reactions in solution that are important in mechanistic studies of RNA-cleaving enzymes. Specifically, we apply DPRc corrections to a base QM model and test its ability to reproduce free-energy profiles generated from a target QM model. We perform these comparisons using the MNDO/d and DFTB2 semiempirical models because they differ in the way they treat orbital orthogonalization and electrostatics and produce free-energy profiles which differ significantly from each other, thereby providing us a rigorous stress test for the DPRc model and training procedure. The comparisons show that accurate reproduction of the free-energy profiles requires correction of the QM/MM interactions out to 6 Å. We further find that the model’s initial training benefits from generating data from temperature replica exchange simulations and including high-temperature configurations into the fitting procedure, so the resulting models are trained to properly avoid high-energy regions. A single DPRc model was trained to reproduce four different reactions and yielded good agreement with the free-energy profiles made from the target QM/MM simulations. The DPRc model was further demonstrated to be transferable to 2D free-energy surfaces and 1D free-energy profiles that were not explicitly considered in the training. Examination of the computational performance of the DPRc model showed that it was fairly slow when run on CPUs but was sped up almost 100-fold when using NVIDIA V100 GPUs, resulting in almost negligible overhead. The new DPRc model and training procedure provide a potentially powerful new tool for the creation of next-generation QM/MM potentials for a wide spectrum of free-energy applications ranging from drug discovery to enzyme design.