Host-guest systems are similar to protein-ligand systems in that they also involve binding of a small molecule to a pocket in a receptor, though they have certain differences. We can think of a host as resembling a very small protein molecule (of different chemistry) which has a binding cavity or pocket. A guest is a small molecule which can bind non-covalently to the host. Supramolecular host families such as the cucurbiturils, cavitands, and cyclodextrins have diverse binding affinities and the ability to bind small drug-like compounds with protein-ligand like affinities . Unlike proteins, the hosts are smaller, simpler, and often more rigid , removing some of the challenges facing computational modeling of proteins. These characteristics make host-guest systems an ideal substitute to test current computational methodologies used to predict physical properties of interest and investigate issues including binding, receptor flexibility, solvation, hydrogen bonding, the hydrophobic effect, protonation, and tautomers . That is, while prediction of protein-ligand binding is still of interest, host-guest systems can serve to help focus on the accuracy of computational methods themselves, without conflating as many other challenges.