Computational Calorimetry: High-Precision Calculation of Host鈥揋uest Binding Thermodynamics

详细信息    查看全文

• 作者：Niel M. Henriksen ; Andrew T. Fenley ; Michael K. Gilson
• 刊名：Journal of Chemical Theory and Computation
• 出版年：2015
• 出版时间：September 8, 2015
• 年：2015
• 卷：11
• 期：9
• 页码：4377-4394
• 全文大小：728K
• ISSN：1549-9626

文摘

We present a strategy for carrying out high-precision calculations of binding free energy and binding enthalpy values from molecular dynamics simulations with explicit solvent. The approach is used to calculate the thermodynamic profiles for binding of nine small molecule guests to either the cucurbit[7]uril (CB7) or 尾-cyclodextrin (尾CD) host. For these systems, calculations using commodity hardware can yield binding free energy and binding enthalpy values with a precision of 鈭?.5 kcal/mol (95% CI) in a matter of days. Crucially, the self-consistency of the approach is established by calculating the binding enthalpy directly, via end point potential energy calculations, and indirectly, via the temperature dependence of the binding free energy, i.e., by the van鈥檛 Hoff equation. Excellent agreement between the direct and van鈥檛 Hoff methods is demonstrated for both host鈥揼uest systems and an ion-pair model system for which particularly well-converged results are attainable. Additionally, we find that hydrogen mass repartitioning allows marked acceleration of the calculations with no discernible cost in precision or accuracy. Finally, we provide guidance for accurately assessing numerical uncertainty of the results in settings where complex correlations in the time series can pose challenges to statistical analysis. The routine nature and high precision of these binding calculations opens the possibility of including measured binding thermodynamics as target data in force field optimization so that simulations may be used to reliably interpret experimental data and guide molecular design.