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

Abstract

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 modeling. The barrel-shaped supramolecular 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 seven commonly abused drugs to the CB8 host, aiming at providing a general picture of CB8−guest binding. 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. A thorough comparison of widely used fixed-charge models for drug-like molecules is presented. 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, and the newly fitted charge set improves the prediction−experiment correlation significantly. 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. The insights of the binding thermodynamics, performance of fixed-charge models, and binding patterns of the CB8−guest systems are useful for studying and elucidating the binding mechanism of other host−guest complexes.

Molecular Modeling of Ionic Liquids: Force‐Field Validation and Thermodynamic Perspective from Large‐Scale Fast‐Growth Solvation Free Energy Calculations

“…Molecular dynamics simulations are becoming a common tool for the investigation of the dynamic and thermodynamic properties of complex biological and chemical systems. [22][23][24][25][26][27][28][29][30][31] In molecular simulations of these green solvents, classical fixedcharge force fields are often incorporated to describe the intraand inter-molecular interactions. [32][33][34][35][36][37][38] The functional forms of classical force fields are simple enough, which enables largescale explorations of long-time dynamics in complex solution systems.…”

Drug Design by Pharmacophore and Virtual Screening Approach

“…Recently, MD simulations have been used to perform a thorough conformational search without any help of traditional docking procedures, with accurate all-atom force field and enhanced sampling techniques, obtaining accurate results for both binding modes and binding affinities [ 47 , 48 ].…”

DFT-D4 Insight into the Inclusion of Amphetamine and Methamphetamine in Cucurbit[7]uril: Energetic, Structural and Biosensing Properties

“…Then, the computational process followed to calculate the most stable configurations (configurations of minimum energy) corresponding to the inclusion complexes of AMP and MET with CB [7] was based on the method developed by Liu and Guo [54]. In addition to Liu and Guo method, other techniques have been developed recently for the theoretical modelling of host-guest binding affinity [55][56][57][58][59][60]. Liu and Guo proposed the semi-empirical methods such as AM1 and PM3, which are fast and could be applied for several positions along the z-axis.…”