SAMPL6 host-guest challenge: binding free energies via a multistep approach
SAMPL6 host-guest challenge: binding free energies via a multistep approach
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DOI：
10.1007/s10822-018-0159-1
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发表时间：
2018-10-01
影响因子：
3.5
通讯作者：
Wilson, Angela K.
中科院分区：
文献类型：
--
作者：
Eken, Yigitcan;Patel, Prajay;Wilson, Angela K.
在SAMPL6主-客体结合挑战中，结合分子动力学和量子力学方法，盲测了一系列瓜环(CB8)、辛酸(OA)和四甲基-辛酸(Temoa)主体在水溶液中与不同客体分子的结合自由能。通过分子动力学(MD)模拟和聚类分析生成了主客体系统的姿势。用MMPBSA方法和密度泛函理论(DFT)计算了分子轨道簇分析得到的结构的结合自由能，其中包括Grimme色散修正、模拟水溶液的隐式溶剂化模型和同一性分辨(RI)近似(分别为MMPBSA、RI-B3PW91-D3和RI-B3PW91)。在这三种方法中，对OA和Temoa体系的结果表明，MMPBSA和RI-B3PW91-D3方法可以分别将具有过结合的小分子的结合能定性地排序7和37kcal/mol，而RI-B3PW91给出的质量最差，这表明色散校正对于结合自由能计算的重要性。由于CB8系统的复杂性，所有的测试方法与实验结果的相关性都很差。其他用于计算结合自由能的量子力学方法包括没有RI近似的DFT，利用截断的基组来减少计算成本(内存、磁盘空间、CPU时间)，以及在隐式溶剂化模型中考虑离子强度的修正的介电常数。
In this effort in the SAMPL6 host-guest binding challenge, a combination of molecular dynamics and quantum mechanical methods were used to blindly predict the host-guest binding free energies of a series of cucurbit[8]uril (CB8), octa-acid (OA), and tetramethyl octa-acid (TEMOA) hosts bound to various guest molecules in aqueous solution. Poses for host-guest systems were generated via molecular dynamics (MD) simulations and clustering analyses. The binding free energies for the structures obtained via cluster analyses of MD trajectories were calculated using the MMPBSA method and density functional theory (DFT) with the inclusion of Grimme's dispersion correction, an implicit solvation model to model the aqueous solution, and the resolution-of-the-identity (RI) approximation (MMPBSA, RI-B3PW91-D3, and RI-B3PW91, respectively). Among these three methods tested, the results for OA and TEMOA systems showed MMPBSA and RI-B3PW91-D3 methods can be used to qualitatively rank binding energies of small molecules with an overbinding by 7 and 37kcal/mol respectively, and RI-B3PW91 gave the poorest quality results, indicating the importance of dispersion correction for the binding free energy calculations. Due to the complexity of the CB8 systems, all of the methods tested show poor correlation with the experimental results. Other quantum mechanical approaches used for the calculation of binding free energies included DFT without the RI approximation, utilizing truncated basis sets to reduce the computational cost (memory, disk space, CPU time), and a corrected dielectric constant to account for ionic strength within the implicit solvation model.