Solvation Free Energy Calculations with Quantum Mechanics/Molecular Mechanics and Machine Learning Models.

For exploration of chemical and biological systems, the combined quantum mechanics and molecular mechanics (QM/MM) and machine learning (ML) models have been developed recently to achieve high accuracy and efficiency for molecular dynamics (MD) simulations. Despite its success on reaction free energy calculations, how to identify new configurations on insufficiently sampled regions during MD and how to update the current ML models with the growing database on the fly are both very important but still challenging. In this article, we apply the QM/MM ML method to solvation free energy calculations and address these two challenges. We employ three approaches to detect new data points and introduce the gradient boosting algorithm to reoptimize efficiently the ML model during ML-based MD sampling. The solvation free energy calculations on several typical organic molecules demonstrate that our developed method provides a systematic, robust, and efficient way to explore new chemistry using ML-based QM/MM MD simulations.