Stable and accurate atomistic simulations of flexible molecules using conformationally generalisable machine learned potentials

Abstract

Computational simulation methods based on machine learned potentials (MLPs) promise to revolutionise shape prediction of flexible molecules in solution, but their widespread adoption has been limited by the way in which training data is generated. Here, we present an approach which allows the key conformational degrees of freedom to be properly represented in reference molecular datasets. MLPs trained on these datasets using a global descriptor scheme are generalisable in conformational space, providing quantum chemical accuracy for all conformers. These MLPs are capable of propagating long, stable molecular dynamics trajectories, an attribute that has remained a challenge. We deploy the MLPs in obtaining converged conformational free energy surfaces for flexible molecules via well-tempered metadynamics simulations; this approach provides a hitherto inaccessible route to accurately computing the structural, dynamical and thermodynamical properties of a wide variety of flexible molecular systems. It is further demonstrated that MLPs must be trained on reference datasets with complete coverage of conformational space, including in barrier regions, to achieve stable molecular dynamics trajectories.