Beijing National Laboratory for Molecular Sciences, Institute of Theoretical and Computational Chemistry, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
XtalPi-AI Research Center (XARC), 9F, Tower A, Dongsheng Building, No. 8, Zhongguancun East Road, Haidian District, Beijing 100083, P.R. China.
J Chem Inf Model. 2021 Dec 27;61(12):6107-6134. doi: 10.1021/acs.jcim.1c01208. Epub 2021 Nov 24.
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.
描述、理解和设计大分子系统内的复杂相互作用网络仍然是现代化学研究中的挑战。尽管主体-客体系统在结构特征和相互作用模式方面相对简单，但在理论建模方面仍然存在问题。桶形超分子容器葫芦[8]脲（CB8）在各种领域（例如催化和分子识别）表现出有前途的功能。它可以稳定地与一系列具有高亲和力的结构多样化的客体配位。在这项工作中，我们研究了七种常见滥用药物与 CB8 主体的结合，旨在提供 CB8-客体结合的总体情况。对这些主体-客体系统的构象空间进行了广泛的采样，并研究了 CB8-客体配合物的结合途径和相互作用模式。还对常用于药物样分子的固定电荷模型进行了全面比较。对原子电荷的迭代拟合表明，电荷产生具有显著的构象依赖性。在原始构象下生成的初始模型可能不适用于构象搜索过程中探索的新构象，而新拟合的电荷集可显著提高预测-实验相关性。我们对 CB8-药物配合物构象空间的研究表明，主体-客体相互作用比预期的更复杂。尽管这些分子的结构简单，但主体和客体分子的构象波动以及官能团的取向导致了一系列结合模式的存在。CB8-客体系统的结合热力学、固定电荷模型的性能和结合模式的见解有助于研究和阐明其他主体-客体配合物的结合机制。
