Transmembrane Permeation Mechanism of Charged Methyl Guanidine.
Transmembrane Permeation Mechanism of Charged Methyl Guanidine.
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DOI：
10.1021/ct400738r
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发表时间：
2014
影响因子：
5.5
通讯作者：
Yukun Wang;Dan Hu;D. Wei
中科院分区：
文献类型：
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作者：
Yukun Wang;Dan Hu;D. Wei
以荷电甲基胍为模型离子，研究了离子跨膜渗透机理。在广泛应用的反应坐标下，我们的伞形采样结果显示，在小的模拟系统中，有限尺寸效应显著，在大的系统中，滞后现象严重。因此，重新审视以往研究中提出的离子跨膜渗透机制的模拟技术是非常重要的。在这项工作中，两个新的集体变量的设计，以获得一个连续的轨迹的渗透过程和小的统计误差，通过伞形抽样。详细讨论了水桥机理。在该机制中，跨膜形成连续的水链（或水分子和脂质头部基团的链）以进行带电甲基胍的跨膜渗透。我们通过在鞍态局部区域的二维伞形采样和在外部区域的一维采样相结合，得到了一个连续的过渡轨迹。我们的自由能分析表明，与水桥的存在下，离子的跨膜渗透的能量势垒显着降低。我们的分析表明，水桥机制是常见的离子渗透穿过厚膜，包括棕榈酰油酰磷酸胆碱和二棕榈酰磷脂酰胆碱膜。
The mechanism of transmembrane ion permeation is studied using charged methyl guanidine as a model ion. With a widely applied reaction coordinate, our umbrella sampling results reveal a significant finite-size effect in small simulation systems and a serious hysteresis in large systems. Therefore, it is important to re-examine the simulation techniques for studying transmembrane permeation mechanism of ions suggested in previous works. In this work, two novel collective variables are designed to acquire a continuous trajectory of the permeation process and small statistical errors through umbrella sampling. A water-bridge mechanism is discussed in detail. In this mechanism, a continuous water chain (or a chain of water molecules and lipid head groups) is formed across the membrane to conduct the transmembrane permeation of charged methyl guanidine. We obtain a continuous transition trajectory by combining the two-dimensional umbrella sampling in the local region of the saddle state and a one-dimensional sampling in the out region. Our free energy analysis shows that, with the presence of the water bridge, the energy barrier of the transmembrane permeation of ions is reduced significantly. Our analysis suggests that the water-bridge mechanism is common for permeation of ions across thick membranes, including palmitoyloleoyl phosphocholine and dipalmitoylphosphatidylcholine membranes.