Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, USA.
J Phys Chem B. 2013 Apr 4;117(13):3578-92. doi: 10.1021/jp400389z. Epub 2013 Mar 26.
Combining umbrella sampling molecular dynamics (MD) simulations, the weighted histogram analysis method (WHAM) for unbiasing probabilities, and polarizable charge equilibration force fields, we compute the potential of mean force for the reversible transfer of methyl guanidinium from bulk solution to the center of a model DPPC bilayer. A 5 kcal/mol minimum in the potential of mean force profile for membrane permeation suggests that the analogue will preferentially reside in the headgroup region of the lipid, qualitatively in agreement with previously published results. We find the potential of mean force for permeation to be approximately 28 kcal/mol (relative to the minimum in the headgroups), within the range of values reported for similar types of simulations using fixed-charge force fields. From analysis of the lipid structure, we find that the lipid deformation leads to a substantial destabilizing contribution to the free energy of the methyl guanidinium as it resides in the bilayer center, though this deformation allows more efficient stabilization by water defects and transient pores. Water in the bilayer core stabilizes the charged residue. The role of water in stabilizing or destabilizing the solute as it crosses the bilayer depends on bulk electrolyte concentration. In 1 M KCl solution, the water contribution to the potential of mean force is stabilizing over the entire range of the permeation coordinate, with the sole destabilizing force originating from the anionic species in solution. Conversely, methyl guanidinium experiences net destabilization from water in the absence of electrolyte. The difference in solvent contributions to permeation free energy is traced to a local effect arising from differences in water density in the bilayer-water solution interface, thus leading to starkly opposite net forces on the permeant. The origin of the local water density differential rests with the penetration of hydrated chloride anions into the solution-bilayer interface. Finally, water permeation into the bilayer is required for the deformation of individual lipid molecules and permeation of ions into the membrane. From simulations where water is first excluded from the bilayer center where methyl guanidinium is restrained and then, after equilibration, allowed to enter the bilayer, we find that in the absence of any water defects/permeation into the bilayer, the lipid headgroups do not follow the methyl guanidinium. Only when water enters the bilayer do we see deformation of individual lipid molecules to associate with the amino acid analogue at bilayer center.
我们结合伞状抽样分子动力学（MD）模拟、无偏概率的加权直方图分析方法（WHAM）以及极化电荷平衡力场，计算了从本体溶液可逆转移到 DPPC 双层膜中心的甲基胍的平均力势。平均力势曲线中出现 5 kcal/mol 的最小值，表明类似物将优先存在于脂质的头基区域，这与先前发表的结果定性一致。我们发现，渗透的平均力势约为 28 kcal/mol（相对于头基中的最小值），处于使用固定电荷力场进行类似模拟报告的值范围内。通过对脂质结构的分析，我们发现，当甲基胍位于双层膜中心时，脂质变形会导致其自由能的显著不稳定贡献，尽管这种变形允许通过水缺陷和瞬态孔更有效地稳定。双层膜核心中的水稳定带电残基。在溶质穿过双层膜时，水是稳定还是不稳定取决于电解质的浓度。在 1 M KCl 溶液中，在整个渗透坐标范围内，水对平均力势的贡献是稳定的，唯一的不稳定力源自溶液中的阴离子物质。相反，在没有电解质的情况下，甲基胍会受到水的净失稳。溶剂对渗透自由能贡献的差异可归因于双层膜-水溶液界面上水密度的局部差异，从而导致对渗透物产生截然相反的净力。局部水密度差别的起源在于水合氯离子穿透进入溶液-双层膜界面。最后，水进入双层膜是单个脂质分子变形和离子渗透进入膜所必需的。从最初将甲基胍约束在双层膜中心并排除水，然后在平衡后允许水进入双层膜的模拟中，我们发现，在没有任何水缺陷/渗透进入双层膜的情况下，脂质头基不会跟随甲基胍。只有当水进入双层膜时，我们才会看到单个脂质分子变形，与双层膜中心的氨基酸类似物结合。
