All-atom Picture of Cucurbituril Detoxification Coordination

The pumpkin-like supra-molecular container Cucurbit[8]uril (CB8) is a promising drug carrier and detoxifier that stably coordinates a series of structurally diverse guests with high association constants. Despite the good biocompatibility of CB8, its practical use is limited by the poor solubility, which could be resolved by methyl substitution Me4CB8. However, this comes with additional difficulties in molecular modelling due to the breaking of the D8h symmetry (to C2v and even lower). The binding-mode space is further complicated by complex structural features of abused drugs (e.g., Fentanyl with multiple aromatic rings). In this work, we present a thorough characterization of cucurbiturils host-guest coordinations on a batch of practical detoxification situations with advanced enhanced sampling techniques in conjunction with the most accurate fixed-charge parameter set, where the water-soluble methylated Me4CB8 is parametrized at B97-3c and the 10 abused drugs are fitted at r2SCAN-3c, achieving a practical accuracy limit of current fixed-charge modelling for cucurbiturils host-guest binding. While the predicted binding thermodynamics agree with experimental values, additional all-atom insights into the binding modes and the nature of host-guest interactions that are absent in experimental measurements are presented in great detail, using a combination of force-field energetics and advanced quantum mechanics-based energy decomposition analysis.