The asymmetry of the hosts and the guests leads to two distinct bound states for each host-guest pair: one where the functional group of the guest sits at the primary face of the host and another where the functional group of the guest sits at the secondary face (18). The difference in binding free energy between these two orientations (ΔΔG orientation ) can be large, at around 2 kcal/mol for SMIRNOFF99Frosst and GAFF v1.7 and 5 kcal/mol for GAFF v2.1. SMIRNOFF99Frosst predicts the largest ΔΔG orientation for the ammoniumcontaining butylamine and pentylamine guests with αCD (4), with the primary orientation being more favorable. Thus, the cationic ammonium groups are predicted to prefer the narrower primary portal of the host. GAFF v1.7 predicts a large ΔΔG orientation for the cyclic alcohols cyclooctanol and cycloheptanol, with the secondary orientation having a more favorable ΔG. When GAFF v2.1 is used, the differences between primary and secondary binding range even higher, greater than 4 kcal/mol, for αCD with these two guests. This effect is due, at least in part, to steric clashes in the bound state for very large guests (Figure , D), especially in the narrow primary cavity of the smaller αCD. It is worth noting that the experimental measurement for the the a-coc (αCD:cyclooctanol) complex has very large uncertainties associated with both ΔG° and ΔH.