Peculiar Aqueous Solubility Trend in Cucurbiturils Unraveled by Atomistic Simulations

Cucurbiturils (CBs) compose a family of macrocycles whose elementary unit is glycouril (GLYC). CBs are of high interest in chemistry and biology due to their versatile applications, ranging from sensors to advanced drug-delivery systems. Here, we report a systematic hydration study of all currently known CBs by classical molecular dynamics simulations to understand their different aqueous solubilities, as revealed in the experiments. Water readily penetrates CBs, including the smallest CB, that is, CB[5]. The number of CB[n]-water hydrogen bonds can be assessed as 2 × n. The hydration enthalpies of the CBs were found to be significantly favorable, due to a number of strong hydrogen bonds with water. However, these enthalpy gains are not enough to compensate for an even larger entropic penalty due to modifying a genuine bulk arrangement of water molecules. We found that the free energy of hydration moderately but uniformly increases with the number of GLYCs. Therefore, the better solubility of odd-numbered CBs is independent of the CB-water interactions, either an enthalpic or entropic contribution. The higher solubilities of CB[n]s with n = 5, 7, or 9 occur exclusively because of their amorphous solid states. Our results allow the prognosis of the aqueous solubilities of not-yet-synthesized CBs.