We hope that training a potential function against host-guest binding data will lead to improved accuracy for protein-ligand binding free energies. We therefore ran ABFE calculations for 59 protein-ligand systems with the original mBondi2 radii and with our HGoptimized radii. We performed these calculations with two AMBER force fields for the protein and two small molecule force fields for the ligands. The results for protein force field ff14SB are illustrated in Figure . As already seen for the host-guest systems, ABFE calculations using OBC2 with its standard mBondi2 radii lead to marked overbinding (i.e., ∆G b too negative). The HSP90 complexes are overestimated the most, with an RMSE of 10 kcal/mol. We suspect this may be related to the importance of an explicit treatment of key water molecules in the binding site. However, further investigation is needed to assess this. Very encouragingly, the new GB radii optimized against host-guest binding data, generate markedly reduced errors for the protein-ligand systems, with the RMSE falling from 7.4 to 2.4 kcal/mol for Sage and from 6.4 to 2.0 kcal/mol for GAFF2. However, the value of R 2 falls by about a factor of 2 using the optimized radii. Thus, the HG-optimized radii transfer reasonably well to protein-ligand systems.