Despite their apparent relative simplicity, host-guest binding has proved a difficult challenge for computation. Large-scale protein-ligand binding free energy studies often report RMS errors in the 1-2 kcal/mol range , which is considerably better than typical performance in SAMPL host-guest challenges . It may be that host-guest systems are "simple" enough that there is essentially nowhere for problems to hide, or confounding factors like polarizability and force field limitations may be more profound in these simple mini-receptors. Alternatively, performance of protein-ligand binding free energy calculations has often been worse in blind challenges like the SAMPL and D3R blind challenges than in the large-scale tests cited above, so it may be that typical retrospective tests simply benefit from participants utilizing additional knowledge which is not available prospectively or in blind challenges. This is supported to some extent by recent benchmarking work from Merck KGaA , and by an earlier industry perspective . Moreover, binding affinities for protein-ligand systems are usually predicted via relative binding free energy calculations for similar ligands. On the other hand, host-guest systems are typically absolute binding free energy calculations and perhaps a reason for the increased difficulty.