Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, Maryland 21201, USA.
J Comput Chem. 2010 Sep;31(12):2330-41. doi: 10.1002/jcc.21527.
Condensed-phase computational studies of molecules using molecular mechanics approaches require the use of force fields to describe the energetics of the systems as a function of structure. The advantage of polarizable force fields over nonpolarizable (or additive) models lies in their ability to vary their electronic distribution as a function of the environment. Toward development of a polarizable force field for biological molecules, parameters for a series of sulfur-containing molecules are presented. Parameter optimization was performed to reproduce quantum mechanical and experimental data for gas phase properties including geometries, conformational energies, vibrational spectra, and dipole moments as well as for condensed phase properties such as heats of vaporization, molecular volumes, and free energies of hydration. Compounds in the training set include methanethiol, ethanethiol, propanethiol, ethyl methyl sulfide, and dimethyl disulfide. The molecular volumes and heats of vaporization are in good accordance with experimental values, with the polarizable model performing better than the CHARMM22 nonpolarizable force field. Improvements with the polarizable model were also obtained for molecular dipole moments and in the treatment of intermolecular interactions as a function of orientation, in part due to the presence of lone pairs and anisotropic atomic polarizability on the sulfur atoms. Significant advantage of the polarizable model was reflected in calculation of the dielectric constants, a property that CHARMM22 systematically underestimates. The ability of this polarizable model to accurately describe a range of gas and condensed phase properties paves the way for more accurate simulation studies of sulfur-containing molecules including cysteine and methionine residues in proteins.
使用分子力学方法对凝聚相分子进行计算研究需要使用力场来描述系统的能量作为结构的函数。极化力场相对于非极化（或加和）模型的优势在于它们能够根据环境的变化而改变其电子分布。为了开发用于生物分子的极化力场，本文提出了一系列含硫分子的参数。通过优化参数来重现气相性质（包括几何形状、构象能、振动光谱和偶极矩）以及凝聚相性质（如蒸发热、分子体积和水合自由能）的量子力学和实验数据。训练集中的化合物包括甲硫醇、乙硫醇、丙硫醇、乙基甲基硫醚和二甲基二硫醚。分子体积和蒸发热与实验值非常吻合，极化模型的性能优于 CHARMM22 非极化力场。极化模型在分子偶极矩和分子间相互作用随取向的处理方面也得到了改进，部分原因是硫原子上存在孤对电子和各向异性原子极化率。极化模型在计算介电常数方面具有显著优势，CHARMM22 系统地低估了介电常数。该极化模型能够准确描述一系列气相和凝聚相性质，为包括蛋白质中半胱氨酸和蛋氨酸残基在内的含硫分子的更准确模拟研究铺平了道路。
