Variational Implicit-Solvent Modeling of Host鈥揋uest Binding: A Case Study on Cucurbit[7]uril|

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• 作者：Shenggao Zhou ; Kathleen E. Rogers ; C茅sar Augusto F. de Oliveira ; Riccardo Baron ; Li-Tien Cheng ; Joachim Dzubiella ; Bo Li ; J. Andrew McCammon
• 刊名：Journal of Chemical Theory and Computation
• 出版年：2013
• 出版时间：September 10, 2013
• 年：2013
• 卷：9
• 期：9
• 页码：4195-4204
• 全文大小：621K
• 年卷期：v.9,no.9(September 10, 2013)
• ISSN：1549-9626

文摘

The synthetic host cucurbit[7]uril (CB[7]) binds aromatic guests or metal complexes with ultrahigh affinity compared with that typically displayed in protein鈥搇igand binding. Due to its small size, CB[7] serves as an ideal receptor鈥搇igand system for developing computational methods for molecular recognition. Here, we apply the recently developed variational implicit-solvent model (VISM), numerically evaluated by the level-set method, to study hydration effects in the high-affinity binding of the B2 bicyclo[2.2.2]octane derivative to CB[7]. For the unbound host, we find that the host cavity favors the hydrated state over the dry state due to electrostatic effects. For the guest binding, we find reasonable agreement to experimental binding affinities. Dissection of the individual VISM free-energy contributions shows that the major driving forces are water-mediated hydrophobic interactions and the intrinsic (vacuum) host鈥揼uest van der Waals interactions. These findings are in line with recent experiments and molecular dynamics simulations with explicit solvent. It is expected that the level-set VISM, with further refinement on the electrostatic descriptions, can efficiently predict molecular binding and recognition in a wide range of future applications.