A General Picture of Cucurbit[8]uril Host–Guest Binding: Recalibrating Bonded Interactions

Atomic-level understanding of the dynamic feature of host–guest interactions remains a central challenge in supramolecular chemistry. The remarkable guest binding behavior of the Cucurbiturils family of supramolecular containers makes them promising drug carriers. Among Cucurbit[n]urils, Cucurbit[8]uril (CB8) has an intermediate portal size and cavity volume. It can exploit almost all host–guest recognition motifs formed by this host family. In our previous work, an extensive computational investigation of the binding of seven commonly abused and structurally diverse drugs to the CB8 host was performed, and a general dynamic binding picture of CB8-guest interactions was obtained. Further, two widely used fixed-charge models for drug-like molecules were investigated and compared in great detail, aiming at providing guidelines in choosing an appropriate charge scheme in host-guest modelling. Iterative refitting of atomic charges leads to improved binding thermodynamics and the best root-mean-squared deviation from the experimental reference is 2.6 kcal/mol. In this work, we focus on a thorough evaluation of the remaining parts of classical force fields, i.e., the bonded interactions. The widely used general Amber force fields are assessed and refitted with generalized force-matching to improve the intra-molecular conformational preference, and thus the description of inter-molecular host–guest interactions. The interaction pattern and binding thermodynamics show a significant dependence on the modelling parameters. The refitted system-specific parameter set improves the consistency of the modelling results and the experimental reference significantly. Finally, combining the previous charge-scheme comparison and the current force-field refitting, we provide general guidelines for the theoretical modelling of host–guest binding.