In the present study, we used the direct approach to computing relative binding enthalpies. This involves simply taking differences between the average energies of free and bound states of the systems . A number of other approaches to computing binding enthalpies have been described , of which perhaps the most common is to compute binding free energies at several different temperatures, and then use in effect the van't Hoff equation to extract the binding enthalpy at a temperature of interest. The potential benefit of the van't Hoff approach is that, because the binding free energy is largely determined by the parts of the simulation system that interact at short range with the ligand, it may scale better with system size than the direct method, which requires converging the energy of the entire system, with all of its complex interactions. On the other hand, it is not trivial to obtain temperature-dependent binding free energies that are numerically precise enough to yield numerically precise binding enthalpies; and in fact, the direct approach was found to be considerably more efficient for host-guest binding systems Another advantage of the direct approach is that, unlike the van't Hoff approach, it allows an informative decomposition of the computed binding enthalpy by system components, as done here, and by energy terms, as done previously . It is also much easier to set up and run a direct enthalpy calculation than a series of binding free energy calculations at multiple temperatures.