Previous work has proposed benchmarking free energy calculations on host-guest systems; for GDCCs, the proposed benchmark included OA binding to guests with adamantane, aromatic, and saturated cyclic carboxylates. These host-guest systems were chosen because of the broad range of binding free energy values produced, and because both host and guests are small and rigid enough to confidently converge binding free energy calculations . Several key challenges were highlighted by prior work: (a) a tight entry/exit portal may create a barrier and prevent entry or exit of guests with bulky hydrophobic cores. Hence, this can hinder sampling of guests leading to convergence problems. (b) It is important to ensure adequate host conformational sampling (though the motions may be slow), particularly of the propionoic acid groups. Benzoic acid flips (at the rim of the cavity) have also been reported from several simulations , though these have not been verified experimentally and may be irrelevant to binding thermodynamics. However, it has been noted that the benzoic acid flips might be an important challenge in some force fields. (c) Waters move only slowly into and out of the cavity, with the number fluctuating over tens of nanoseconds . (d) Salt concentration and buffer conditions may modulate binding to GDCCs. Additionally, (e) charged guests may introduce finite-size artifacts. (f) Strong electrostatic interactions could result in modified protonation states of the host and/or guest. Acidic guests could be protonated, or two of the propionate groups could retain an acidic proton because they are in close proximity and can hydrogen bond. At the rim of the cavity a guest may also modulate protonation state of the neighboring carboxylates.