Stabilization of Guest Molecules inside Cation-Lidded Cucurbiturils Reveals that Hydration of Receptor Sites Can Impede Binding

Docking of alkali metal ions to water-soluble macrocyclic receptors generally reduces the affinity of guest molecules due to competitive binding. The idea that solvation water molecules could display a larger steric hindrance towards guest binding than cations has not been considered to date. We show that the docking of large cations to cucurbit[5]uril (CB5) unexpectedly increases (by a factor of 5–8) the binding of hydrophobic guests, methane and ethane. This is due to the removal of water molecules from the carbonyl portals of CB5 during cation binding, which frees up space for hydrophobe encapsulation. In contrast, smaller cations like sodium protrude deeply into the cavity of CB5 and cause the expected decrease in binding, such that the rational selection of alkali cations allows for a variation of up to a factor of 20 in binding of methane and ethane. The statistical analysis of crystallographic data shows that the cavity volume of CB5 can be enlarged by placing large alkali ions (Rb+ and Cs+) centro-symmetrically at the portals. The results reveal a hitherto elusive steric hindrance of solvation water molecules near receptor binding sites, which is pertinent for the design of supramolecular catalysts and the understanding of biological receptors.