As we improve representations of other macromolecules it will be increasingly important to consider other sources of entropy, including solvent and ligands. Much attention has been focused on the behavior at the binding site, with reduction of the ligand ensemble into a single state being countered by the displacement of ordered water molecules. However, in high-resolution X-ray crystallography data, multiple conformations of ligands are often detected in binding sites, suggesting that many protein-ligand complexes have multiple binding states and indicating that ligand binding results in less entropic loss than previously believed. Additionally, as seen in the FaDH model, solvent plays a critical role beyond the binding site. To gain a deeper insight into the entropic implications of solvent interactions, it is crucial to refine our modeling and thermodynamic interpretation of first and second shell water molecules, particularly those in exchange with the bulk solvent and thus 'partially occupied', as revealed by molecular dynamics (MD) simulations . Creating a more atomistic model of the entropic contributions of solvent may reconcile outlier observations in the entropy meter, which links side chain dynamics to experimental ITC data, and move us closer to predicting the entropic impact of a perturbation.