The Sage force field provides competitive accuracy in relative binding free energy calculations, as shown in Figure where performance of the force fields is summarized according to absolute binding free energy differences back-calculated from the ΔΔG estimates. Indeed, the accuracies of the four force fields examined here (Parsley 1.0.0, Sage 2.0.0, GAFF2.1x/AM1-BCC, and OPLS3e) are within 95% confidence intervals of each other. It is important to note that the accuracy of these calculations is strongly affected by additional factors, including input structure preparation and sampling time. In addition, protein force field, water model and partial charge assignment in Sage (OpenFF 2.0.0) were identical to those used with Parsley 1.0.0. Given these considerations, we did not necessarily expect here that improvements in the small molecule force field would dramatically impact the accuracy of calculated binding free energies. In particular, our main goal was to ensure that the substantial refit of LJ parameters done in the present effort did not adversely affect accuracy of these calculations, while improving accuracy in more direct measures of force field quality. We also note that the accuracy for these calculations depends on the protein-ligand system, ranging from an RMSE = 0.57 kcal mol -1 for target galectin to RMSE = 2.62 kcal mol -1 for target PDE10 using the Sage 2.0.0 force field (SI Table ). In terms of overall RMSE across all targets for binding free energy Δ𝐺 • , Sage (RMSE=1.29 [1.17 The metrics are based on the binding free energies Δ𝐺 calculated from relative ΔΔ𝐺 values (1133 values for each force field) with Arsenic (now called Cinnabar). The presented force fields are Parsley 1.0.0, Sage 2.0.0, GAFF2.1x/AM1-BCC, and OPLS3e (specific versions of GAFF2.1x given in SI for each system).