Ali Hafiz Saqib, Higham Jonathan, de Visser Sam P, Henchman Richard H
Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, United Kingdom.
Department of Chemistry, The University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom.
J Phys Chem B. 2020 Aug 6;124(31):6835-6842. doi: 10.1021/acs.jpcb.0c02264. Epub 2020 Jul 27.
Calculating the free-energy barriers of liquid-phase chemical reactions with explicit solvent is a considerable challenge. Most studies use the energy and entropy of minimized single-point geometries of the reactants and transition state in implicit solvent using normal mode analysis (NMA). Explicit-solvent methods instead make use of the potential of mean force (PMF). Here, we propose a new energy-entropy (EE) method to calculate the Gibbs free energy of reactants and transition states in explicit solvent by combining quantum mechanics/molecular mechanics (QM/MM) molecular dynamics simulations with multiscale cell correlation (MCC). We apply it to six nucleophilic substitution reactions of the hydroxide transfer to methyl and ethyl halides in water, where the halides are F, Cl, and Br. We compare EE-MCC Gibbs free energy barriers using two Hamiltonians, self-consistent charge density functional based tight-binding (SCC-DFTB) and B3LYP/6-31+G* density functional theory (DFT) with respective PMF values, EE-NMA values using B3LYP/6-31+G* and M06/6-31+G* DFT in implicit solvent and experimental values derived via transition state theory. The barriers using SCC-DFTB are found to agree well with the PMF and experiment and previous computational studies, being slightly higher but improving on the lower values obtained for the implicit solvent. Achieving convergence over many degrees of freedom remains a challenge for EE-MCC in explicit-solvent QM/MM systems, particularly for the more expensive B3LYP/6-31+G* and M06/6-31+G* DFT methods, but the insightful decomposition of entropy over all degrees of freedom should make EE-MCC a valuable tool for deepening the understanding of chemical reactions.
使用显式溶剂计算液相化学反应的自由能垒是一项颇具挑战性的任务。大多数研究使用隐式溶剂中反应物和过渡态的最小化单点几何结构的能量和熵，并采用简正模式分析（NMA）。相反，显式溶剂方法利用平均力势（PMF）。在此，我们提出一种新的能量 - 熵（EE）方法，通过将量子力学/分子力学（QM/MM）分子动力学模拟与多尺度细胞关联（MCC）相结合，来计算显式溶剂中反应物和过渡态的吉布斯自由能。我们将其应用于水中氢氧化物向甲基和乙基卤化物转移的六个亲核取代反应，其中卤化物为F、Cl和Br。我们使用两种哈密顿量，即基于自洽电荷密度泛函紧束缚（SCC - DFTB）和B3LYP/6 - 31 + G密度泛函理论（DFT），将EE - MCC吉布斯自由能垒与各自的PMF值、在隐式溶剂中使用B3LYP/6 - 31 + G和M06/6 - 31 + G* DFT的EE - NMA值以及通过过渡态理论得到的实验值进行比较。发现使用SCC - DFTB得到的能垒与PMF以及实验结果和先前的计算研究结果吻合良好，略高于隐式溶剂中得到的较低值但有所改进。在显式溶剂QM/MM系统中，对于EE - MCC而言，在多个自由度上实现收敛仍然是一个挑战，特别是对于更昂贵的B3LYP/6 - 31 + G和M06/6 - 31 + G DFT方法，但对所有自由度上熵的深入分解应该使EE - MCC成为深化对化学反应理解的有价值工具。
