A General Picture of Cucurbit[8]uril Host-Guest Binding

Describing, understanding, and designing complex interaction networks within macromolecular systems remain challenging in modern chemical research. Host-guest systems, despite their relative simplicity in both the structural feature and interaction patterns, still pose problems in theoretical modelling. The barrel-shaped supra-molecular container Cucurbit[8]uril (CB8) shows promising functionalities in various areas, e.g., catalysis and molecular recognition. It can stably coordinate a series of structurally diverse guests with high affinities. In this work, we examine the binding of 7 commonly abused drugs to the CB8 host, aiming at providing a general picture of CB8-guest binding. A thorough comparison of widely used fixed-charge models for drug-like molecules is presented. Extensive sampling of the configurational space of these host-guest systems is performed, and the binding pathway and interaction patterns of CB8-guest complexes are investigated in detail. Iterative refitting of the atomic charges suggests significant conformation-dependence of charge generation. The initial model generated at the original conformation could be inaccurate for new conformations explored during conformational search. Our investigations of the configurational space of CB8-drug complexes suggest that the host-guest interactions are more complex than expected. Despite the structural simplicities of these molecules, the conformational fluctuations of the host and the guest molecules and orientations of functional groups lead to the existence of an ensemble of binding modes (e.g., bracelet-like guest conformations and crescent free energy landscapes). Thus, understandings obtained from static calculations based on a single or several structures are limited for these host-guest interactions. The investigation protocol provides useful guidelines for studying host-guest binding, and the insights of the binding thermodynamics, performance of fixed-charge models, and binding patterns of the CB8-guest systems are useful for elucidating the binding mechanism of other host-guest complexes.