Department of Pharmaceutical Sciences, School of Pharmacy , University of Maryland , 20 Penn Street , Baltimore , Maryland 21201 , United States.
Department of Biochemistry and Molecular Biology , University of Chicago , Chicago , Illinois , 60637 , United States.
J Chem Inf Model. 2018 May 29;58(5):993-1004. doi: 10.1021/acs.jcim.8b00132. Epub 2018 Apr 17.
Development of accurate force field parameters for molecular ions in the context of a polarizable energy function based on the classical Drude oscillator is a crucial step toward an accurate polarizable model for modeling and simulations of biological macromolecules. Toward this goal we have undertaken a hierarchical approach in which force field parameter optimization is initially performed for small molecules for which experimental data exists that serve as building blocks of macromolecular systems. Small molecules representative of the ionic moieties of biological macromolecules include the cationic ammonium and methyl substituted ammonium derivatives, imidazolium, guanidinium and methylguanidinium, and the anionic acetate, phenolate, and alkanethiolates. In the present work, parameters for molecular ions in the context of the Drude polarizable force field are optimized and compared to results from the nonpolarizable additive CHARMM general force field (CGenFF). Electrostatic and Lennard-Jones parameters for the model compounds are developed in the context of the polarizable SWM4-NDP water model, with emphasis on assuring that the hydration free energies are consistent with previously reported parameters for atomic ions. The final parameters are shown to be in good agreement with the selected quantum mechanical (QM) and experimental target data. Analysis of the structure of water around the ions reveals substantial differences between the Drude and additive force fields indicating the important role of polarization in dictating the molecular details of aqueous solvation. The presented parameters represent the foundation for the charged functionalities in future generations of the Drude polarizable force field for biological macromolecules as well as for drug-like molecules.
在基于经典 Drude 振荡器的可极化能量函数的背景下，为分子离子开发准确的力场参数是为生物大分子建模和模拟构建准确可极化模型的关键步骤。为此，我们采用了一种分层方法，首先针对具有实验数据的小分子进行力场参数优化，这些实验数据可作为大分子系统的构建块。代表生物大分子离子部分的小分子包括阳离子铵和甲基取代的铵衍生物、咪唑鎓、胍鎓和甲基胍鎓，以及阴离子乙酸盐、苯酚盐和烷硫醇盐。在本工作中，优化了 Drude 可极化力场中分子离子的参数，并将其与非极化加性 CHARMM 通用力场（CGenFF）的结果进行了比较。在可极化 SWM4-NDP 水模型的背景下，为模型化合物开发了静电和 Lennard-Jones 参数，重点是确保水合自由能与以前报道的原子离子参数一致。最终参数与选定的量子力学（QM）和实验靶数据吻合良好。对离子周围水的结构分析表明，Drude 和加性力场之间存在显著差异，表明极化在决定水溶剂化的分子细节方面起着重要作用。所提出的参数为未来生物大分子 Drude 可极化力场以及类似药物分子的带电功能奠定了基础。
