We performed all MD simulations with the OpenMM MD engine version 7.5.1. Except for the protein-ligand binding calculations, the OpenMM simulations were run through the OpenFF-Evaluator framework. For the hydration free energy and host-guest binding affinity calculations, we use the Sage (OpenFF 2.0.0 61 ) force field from OpenFF with AM1-BCC 62,63 partial charges and ELF10 (electrostatically least-interacting functional) conformer selection. Partial charges were assigned to the small molecules with the OpenFF-Toolkit using OpenEye OEChem (version 2022) as its backend. We ran four sets of calculations for each protein-ligand system, the result of testing two AMBER force fields for the protein, i.e., .