Calculations of solvation free energies (Δ𝐺 𝑠𝑜𝑙𝑣 ) used the YANK alchemical simulation software package, version 0.25.2, and the same OpenFF Evaluator workflow as used in Boothroyd et al. These calculations used a thermodynamic cycle that involved 2 simulation steps: 1) the removal of a solute molecule from a box of solvent and 2) the annihilation of a solute molecule from a vacuum box. For step 1, the simulation box contained 2000 molecules of solvent and a single molecule of solute. The solute was removed along an alchemical pathway which gradually turned off the nonbonded interactions along a soft-core alchemical schedule. The implementations of the alchemical pathway and values of 𝜆 are handled by the openmmtools software package version 0.20.3. We also assessed the performance of the newly fitted Sage force field in relative binding free energy calculations based on molecular dynamics simulations following suggested best practices for benchmarking binding affinities. Relative binding free energies were calculated employing alchemical perturbations between pairs of ligands in water and the protein complex. These calculations employed a non-equilibrium workflow based on GROMACS and pmx as described previously. For the ligand molecules, the Sage 2.0.0 force field was used. The protein was parameterized with the AMBER ff99sb*-ILDN force field and a TIP3P explicit water model was employed. We chose AMBER ff99sb*-ILDN as the protein force field because Parsley and Sage are essentially AMBER-family force fields and should be compatible, or nearly so, with AMBER protein force fields. Indeed, benchmarking on protein-ligand binding free energies here aimed to test this compatibility. The water model was chosen as TIP3P due to the widespread use of this water model with the AMBER family of protein force fields and because TIP3P was used in fitting to condensed phase properties described in this paper. To mimic physiological conditions, ions (150 mM NaCl ) and additional counterions to neutralize the system were added to the dodecahedral simulation boxes.