An ideal set of GB cavity radii would provide not only accurate binding free energies but also accurate HFEs. We tested this by using both the original (mBondi2) and HG-optimized radii to estimate ∆G solv for 100 neutral small molecules from the FreeSolv database (see Methods 2.4), using the Sage small molecule force field. As shown in Figure , the original mBondi2 radii give good accuracy, with an RMSE of 2.1 kcal/mol and R 2 of 0.8. However, the HG-optimized radii yield marked overestimation of the magnitudes of the HFEs (Figure ), ∆G solv , increasing the RMSE to 19.1 kcal/mol and decreasing the R 2 to 0.4. Thus, fitting GB cavity radii to host-guest ∆G b improves the accuracy of ABFE calculations, but this improvement comes at the cost of lower accuracy in ∆G solv .