Reliably evaluating the most stable conformations of charged small organic molecules in solution poses a major challenge to computational chemistry, due to limitations in the accuracy or efficiency of conventional methodologies. In this paper, we present a hybrid machine learning/molecular mechanics (ML/MM) potential, with dynamic, conformationally dependent charges on the atoms in the ML region, that can be used to address this important challenge in drug design. By way of a case study, metadynamics-enhanced molecular dynamics simulations were used to compare the performance of several intermolecular potentials in evaluating the solution phase conformational free energy differences of pharmaceutically relevant ligands based on the protonated 2-phenylethylamine scaffold. A straightforward approach to an ML/MM potential, in which the solute's intramolecular interactions are substituted by an ML model and making no other modifications to the force field, yields results inferior to a conventional fixed-charge MM potential, due to an imbalance created in the intra- and intermolecular interactions. To remedy this shortcoming, we present a new ML/MM potential that combines an accurate, trained-for-purpose ML model (PairFEQ-Net) of the charged ligand, with the polarizable SWM3 MM model of water. Crucially, by employing an empirical parameter to scale gas phase charges, the ML model predicts dynamic, solvent-polarized charges that embed the ligand in the solvent in a more balanced way. This ML/MM potential results in mean absolute errors in the prediction of conformational free energies of just 0.5 kcal mol-1, hence furnishing a possible route to the chemically accurate prediction of the shapes of charged organic molecules in aqueous solution.
Williams et al. (Thu,) studied this question.