From here, one can take different strategies toward further improvement of the implicit solvent model -a goal that we believe is well justified, given the 10x speedup of ABFE calculations that it affords. We suspect that it will be impossible to accurately fit both ABFEs and HFEs with the OBC2 model, but a model optimized for binding and not hydration may be of value, since binding affinities are certainly of more practical importance than the HFEs of small molecules. Our HG-optimized radii work well for binding already, but to improve the model further, one could increase the diversity of the training data to include host-guest complexes with other host molecule types and possibly include protein-ligand binding as well. The former can be done by adding more systems to Taproom, while the latter will require extending the Evaluator framework to include a protein-ligand binding affinity workflow. Including some protein-ligand binding in the training data would avoid the risk of overfitting to host-guest systems and might resolve the excessive protein flexibility observed in Figure . On the other hand, it may be difficult to arrive at a set of GB cavity radii that, when used with the standard OBC2 model, improves not only RMSE but also R 2 for protein-ligand systems, because changes in hydration are particularly marked for protein-ligand binding Thus, it would be preferable to derive an implicit solvent model that can reproduce both ABFEs and HFEs, and we anticipate that such a model could yield further improvement in the accuracy of ABFE calculations because hydration certainly contributes to the balance of forces that determine the overall binding affinity. To accomplish this, one may need to modify the functional forms of the GB model. Accordingly, we are currently looking for better alternatives to the traditional GB kernel, f GB in Eq (2) and to the formula used to compute the effective radii R i in Eq (3). The simplest changes to these functional forms would retain their radially symmetric character, so that the solvation free energy depends explicitly only on interatomic distances, rather than on the angular distributions of atoms around each other. Given the directionality of solute-water hydrogen bonds, it may ultimately be important to use information about the angular distributions of atoms around each other as well.