Tips and Tricks for Small Molecule and Force Field Parametrization

Abstract

In order to be productive in drug design and materials science, molecular dynamics force fields need to possess quality and fidelity that allow researchers to observe phenomena in simulation before observing them in experiment. The inverse scenario parameters and force fields that are of low quality and fidelity – leads researchers away from the underlying molecular mechanisms they are looking for towards spurious phenomena that are mere artifacts of the flaws and deficiencies of the potential energy functions. Obtaining high quality parameters and potentials and rigorously establishing that they are of high quality and predictive capacity, however, is a daunting task that involves navigating a highly complex, multidimensional hyperspace of decisions and parameters. Here, we demonstrate several cost-effective means of obtaining and validating parameters for ions and small molecules in all-atom molecular dynamics simulations. First, using calculated and experimental hydration free energies (HFEs) for 23 challenging small molecules, we show that RESP charges considerably improve agreement with experiment compared to AM1-BCC charges. In addition, we highlight the danger of using unreliable data such as ion HFEs and imprecise methods such as the saturation concentration in mixed crystal-solution systems to calibrate force field parameters. Instead, we propose metrics that can be accurately measured experimentally and reliably calculated, namely ionic salt densities and ion pair free energies. Switching from unreliable and imprecise to highly accurate and reliable calibratory data will further improve the quality and utility of molecular modeling and simulation in future drug design and materials science research.