For the complex simulations, a similar pattern is seen for the mean energy of the combined binding site and ligand, u BLi P Li , and of the binding site alone, u B P Li , as these have larger SEMs in general than those of the full simulated systems (Table ). Again, this points to anticorrelation of these energy components with other energy components present in the full systems. However, the mean energies of the ligands alone, u Li Li , appear better converged. It is of interest that the uncertainties of the binding site and ligand together ( u BLi P Li ) are greater than those of the binding site and ligand separately ( u B P Li , u Li P Li ). The difference likely traces to large fluctuations in the ligand-binding site interaction energies, ∆u inter,i , which are not present in the internal energies of the separate binding site and ligand. Inspection of the trajectories shows that parts of the ligands sometimes detach from the binding site, and then reattach. Such motions would indeed lead to large changes in the ligand-binding site interaction energies, along with anticorrelated changes in the ligand's and binding site's interactions with the solvent.