Quantum-based machine learning and AI models to generate force field parameters for drug-like small molecules

Abstract

Force fields for drug-like small molecules play an essential role in molecular dynamics simulations and binding free energy calculations. In particular, the accurate generation of partial charges on small molecules is critical to understanding the interactions between proteins and drug-like molecules. However, it is a time-consuming process. Thus, we generated a force field for small molecules and employed a machine learning (ML) model to rapidly predict partial charges on molecules in less than a minute of time. We performed density functional theory (DFT) calculation for 31770 small molecules that covered the chemical space of drug-like molecules. The partial charges for the atoms in a molecule were predicted using an ML model trained on DFT-based atomic charges. The predicted values were comparable to the charges obtained from DFT calculations. The ML model showed high accuracy in the prediction of atomic charges for external test data sets. We also developed neural network (NN) models to assign atom types, phase angles and periodicities. All the models performed with high accuracy on test data sets. Our code calculated all the descriptors that were needed for the prediction of force field parameters and produced topologies for small molecules by combining results from ML and NN models. To assess the accuracy of the predicted force field parameters, we calculated solvation free energies for small molecules, and the results were in close agreement with experimental free energies. The AI-generated force field was effective in the fast and accurate generation of partial charges and other force field parameters for small drug-like molecules.