Machine Learning Estimates of Natural Product Conformational Energies

Machine learning has been used for estimation of potential energy surfaces to speed up molecular dynamics simulations of small systems. We demonstrate that this approach is feasible for significantly larger, structurally complex molecules, taking the natural product Archazolid A, a potent inhibitor of vacuolar-type ATPase, from the myxobacterium Archangium gephyra as an example. Our model estimates energies of new conformations by exploiting information from previous calculations via Gaussian process regression. Predictive variance is used to assess whether a conformation is in the interpolation region, allowing a controlled trade-off between prediction accuracy and computational speed-up. For energies of relaxed conformations at the density functional level of theory (implicit solvent, DFT/BLYP-disp3/def2-TZVP), mean absolute errors of less than 1 kcal/mol were achieved. The study demonstrates that predictive machine learning models can be developed for structurally complex, pharmaceutically relevant compounds, potentially enabling considerable speed-ups in simulations of larger molecular structures.Author Summary: Molecular dynamics simulations provide insight into the dynamic behavior of molecules, e.g., into the adopted spatial arrangements of its atoms over time. Methods differ in the approximations they employ, resulting in a trade-off between accuracy and speed that ranges from highly accurate but expensive quantum mechanical calculations to fast but more inaccurate molecular mechanics force fields. Machine learning, a sub-discipline of artificial intelligence, provides algorithms that learn from data, that is, make predictions based on previously seen examples. By starting with a few expensive quantum mechanical calculations, training a machine learning algorithm on them, and then using the resulting model to carry out the molecular dynamics simulation, one can improve the accuracy/speed trade-off. We have developed and applied such a hybrid quantum mechanics/machine learning approach to Archazolid A, a natural product from the myxobacterium Archangium gephyra and a potent inhibitor of vacuolar-type ATPase. By dynamically refining our model over the course of the simulation, we achieve errors of less than 1 kcal/mol while saving over 40% of the quantum mechanical calculations. Our study demonstrates the feasibility of predictive machine learning models for the dynamics of structurally complex, pharmaceutically relevant compounds, potentially enabling considerable speed-ups in simulations of even larger biomolecular structures.