Department of Chemistry, Michigan State University, East Lansing, MI, 48864, USA.
Department of Chemistry, University of North Texas, Denton, TX, 76201, USA.
J Comput Aided Mol Des. 2021 Jan;35(1):63-77. doi: 10.1007/s10822-020-00357-3. Epub 2020 Nov 5.
Statistical Assessment of Modeling of Proteins and Ligands (SAMPL) challenges provide routes to compare chemical quantities determined using computational chemistry approaches to experimental measurements that are shared after the competition. For this effort, several computational methods have been used to calculate the binding energies of Octa Acid (OA) and exo-Octa Acid (exoOA) host-guest systems for SAMPL7. The initial poses for molecular dynamics (MD) were generated by molecular docking. Binding free energy calculations were performed using molecular mechanics combined with Poisson-Boltzmann or generalized Born surface area solvation (MMPBSA/MMGBSA) approaches. The factors that affect the utility of the MMPBSA/MMGBSA approaches including solvation, partial charge, and solute entropy models were also analyzed. In addition to MD calculations, quantum mechanics (QM) calculations were performed using several different density functional theory (DFT) approaches. From SAMPL6 results, B3PW91-D3 was found to overestimate binding energies though it was effective for geometry optimizations, so it was considered for the DFT geometry optimizations in the current study, with single-point energy calculations carried out with B2PLYP-D3 with double-, triple-, and quadruple-ζ level basis sets. Accounting for dispersion effects, and solvation models was deemed essential for the predictions. MMGBSA and MMPBSA correlated better to experiment when used in conjunction with an empirical/linear correction.
统计评估蛋白质和配体建模（SAMPL）挑战为比较使用计算化学方法确定的化学量与竞争后共享的实验测量提供了途径。为此，已经使用了几种计算方法来计算 SAMPL7 中 Octa Acid (OA) 和 exo-Octa Acid (exoOA) 主体 - 客体系统的结合能。分子动力学（MD）的初始构象通过分子对接生成。使用分子力学结合泊松-玻尔兹曼或广义 Born 表面面积溶剂化（MMPBSA/MMGBSA）方法进行结合自由能计算。还分析了影响 MMPBSA/MMGBSA 方法效用的因素，包括溶剂化、部分电荷和溶质熵模型。除了 MD 计算外，还使用几种不同的密度泛函理论（DFT）方法进行量子力学（QM）计算。从 SAMPL6 的结果来看，尽管 B3PW91-D3 对结合能的估计过高，但它对几何优化很有效，因此在当前研究中考虑将其用于 DFT 几何优化，使用带有双、三、四 ζ 水平基组的 B2PLYP-D3 进行单点能计算。考虑到色散效应和溶剂化模型对于预测至关重要。当与经验/线性校正结合使用时，MMGBSA 和 MMPBSA 与实验的相关性更好。
