Neural Network Potential with Multiresolution Approach Enables Accurate Prediction of Reaction Free Energies in Solution

We present the design and implementation of a novel neural network potential (NNP) and its combination with an electrostatic embedding scheme, commonly used within the context of hybrid quantum-mechanical/molecular-mechanical (QM/MM) simulations. Substitution of a computationally expensive QM Hamiltonian by an NNP with the same accuracy largely reduces the computational cost and enables efficient sampling in prospective MD simulations, the main limitation faced by traditional QM/MM setups. The model relies on the recently introduced anisotropic message passing (AMP) formalism to compute atomic interactions and encode symmetries found in QM systems. AMP is shown to be highly efficient in terms of both data and computational costs and can be readily scaled to sample systems involving more than 350 solute and 40,000 solvent atoms for hundreds of nanoseconds using umbrella sampling. Most deviations of AMP predictions from the underlying DFT ground truth lie within chemical accuracy (4.184 kJ mol–1). The performance and broad applicability of our approach are showcased by calculating the free-energy surface of alanine dipeptide, the preferred ligation states of nickel phosphine complexes, and dissociation free energies of charged pyridine and quinoline dimers. Results with this ML/MM approach show excellent agreement with experimental data and reach chemical accuracy in most cases. In contrast, free energies calculated with static DFT calculations paired with implicit solvent models or QM/MM MD simulations using cheaper semiempirical methods show up to ten times higher deviation from the experimental ground truth and sometimes even fail to reproduce qualitative trends.