The challenge of getting the relative binding enthalpies right may stem in part from the fact that these quantities are a balance of large, opposing contributions from different structural components, such as the ligand-binding site interactions and the internal binding site energies, much as previously noted in the context of host-guest binding . Thus, the net, relative binding enthalpies may be sensitive to small shifts in these large, opposing energy components. That binding is a small balance of large components may be understood by recognizing that binding of a ligand leads to the formation of strong new ligand-protein interactions, as well as new solvent-solvent interactions made by displaced water molecules. These negative energy changes are at least partly balanced by positive contributions from the loss of favorable ligand-solvent and protein-solvent interactions. A related observation is that the variances of the overall energies are smaller than those of the component energies, even though the latter derive from far fewer atoms. This means that the energy fluctuations of the various components are strongly anticorrelated with each other, a phenomenon which may be understood based on similar reasoning.