Determination of candidates to advance through the drug development pipeline consumes years of time and resources. Scientists must identify and filter through thousands of candidate compounds through vigorous validation experiments to eventually have one clinically approved drug. Physics-based methods such as protein-ligand binding free energy calculations have been increasingly adopted in early-stage drug discovery to reduce the time and cost of the early stages of drug discovery by reducing the number of costly experiments. Binding free energy calculations such as relative binding free energy (RBFE) calculation methods serve to prioritize related compounds through their binding a nity. The accuracy of these methods are highly dependent on the methods used and choices made while preparing the ligands and protein ahead of running calculations. Most commonly, free energy methods use classical all-atom force fields which model interactions as a combination of valence terms (bond, angle, and torsional potentials), Lennard-Jones interactions, and classical Coulombic interactions from atom-centered partial atomic charges.