The accuracy of free energy calculations is dependent on and limited by inaccuracy in the energy model used (i.e., force field used, finite-size effects, and water model) , sampling, and the protein-ligand system set up, which can include aspects such as protonation state, chosen tautomer state, and buffer, to name a few . Although sources of systematic error in free energy calculations are known, it is difficult to analyze errors when modeling protein-ligand systems due to their flexibility and complexity; such challenges mean that simulations of a few nanoseconds to microseconds may not always adequately sample the relevant conformations of the protein, ligand and environment . For this reason, host-guest systems are a great substitute for protein-ligand systems in evaluations of computational methods for predicting free energies of binding , as conformational sampling can be less of a challenge.