One of the enabling -or limiting -factors in the utility of computer modeling and allatom molecular dynamics simulations for the purposes of drug design and discovery is the fidelity and accuracy of the potentials used in these campaigns. On the one end of the computational spectrum, we have molecular docking -a popular and conceptually simple technique used to rapidly screen libraries of ligands against a target of interest. Docking typically employs unsophisticated, easily computable empirical or knowledge-based potentials to evaluate different ligand conformations and rank all the ligands in a library. On the other extreme, we have the theoretically rigorous and computationally demanding absolute binding free energy calculations (ABFEs) . Typically, docking tries to discern ligands that bind to the target of interest from ones that do not by rapidly evaluating simple scoring functions while ABFEs try to accurately calculate, at least in principle, the absolute free energy of binding (ΔGbind or simply ΔG) between the target and every ligand being screened by covering the relevant conformational space and evaluating ΔGbind using potential energy functions referred to as force fields. In principle, ΔGbind is the difference between the free energy (G) of the bound state and the free energy of the unbound protein and unbound ligand in solution. In practice, ABFEs do not calculate absolute free energies (Gs) but only free energy changes or differences (ΔGs) by constructing a thermodynamic cycle and decoupling the ligand from the bound state and from solvent and taking the difference of these two terms . The free energy change upon decoupling the ligand from solvent, i.e. desolvating the ligand, is the desolvation free energy or the solvation free energy multiplied by -1. In the case where the solvent is water, what is being calculated is the (de)hydration free energy (HFE). In contrast to ABFEs, where the ligand is decoupled from the system, in relative binding free energy (RBFE) calculations, the ligand is transformed into a different ligand, typically a close analog, in order to calculate the relative change in free energy (ΔΔG) between the two .