Another aspect of MolDarting that we will need to address in future work is the use of im-plicit solvent. Here, we used implicit solovent because it offers a way to represent the effects of solvent without actually having solvent particles present. Thus, when using MolDarting with implicit solvent we avoided having to displace waters in the binding site when restoring the ligand's interactions during NCMC, alleviating potential sampling problems. Implicit solvent simulations, however, are not without their limitations. Since implicit solvent aims to represent the bulk properties of water, interactions that depend on individual water molecules, like those often present in protein binding pockets, may not be well represented. However, there are a number of different circumstances that the implicit solvent representation could still yield reasonable results. One situation is when the ligand binding pocket is in an internal cavity that contains no water. While uncommon, these types of binding pockets do exist, such as in the model binding system T4 Lysozyme L99A and myoglobin. Another case would be when the binding site waters are bulk-like and are well described by an implicit solvent model. Still, for the best accuracy we expect to need to eventually move to explicit solvent and deal with any associated water sampling challenges.