Gurtovenko Andrey A, Vattulainen Ilpo
Computational Laboratory, Institute of Pharmaceutical Innovation, University of Bradford, Bradford, West Yorkshire, BD7 1DP, United Kingdom.
Biophys J. 2007 Mar 15;92(6):1878-90. doi: 10.1529/biophysj.106.094797. Epub 2007 Jan 5.
We have employed atomic-scale molecular dynamics simulations to address ion leakage through transient water pores in protein-free phospholipid membranes. Our results for phospholipid membranes in aqueous solution with NaCl and KCl salts show that the formation of transient water pores and the consequent ion leakage can be induced and be driven by a transmembrane ionic charge imbalance, an inherent feature in living cells. These processes take place if the gradient is large enough to develop a sufficiently significant potential difference across the membrane. The transport of cations and anions through the water pores is then seen; it discharges the transmembrane potential, considerably reduces the size of a water pore, and makes the water pore metastable, leading eventually to its sealing. The ion transport is found to be sensitive to the type of ions. It turns out that Na(+) and Cl(-) ions leak through a membrane at approximately the same ratio despite the fact that Na(+) ions are expected to experience a lower potential barrier for the permeation through the pore. This is because of strong interactions of sodium ions with the carbonyl region of a phospholipid membrane as well as with lipid headgroups forming pore "walls," considerably slowing down the permeation of sodium ions. In contrast, we observed a pronounced selectivity of a phospholipid membrane to the permeation of potassium ions as compared to chloride ions: Potassium ions, being larger than sodium ions, interact only weakly with phospholipid headgroups, so that these interactions are not able to compensate for a large difference in free-energy barriers for permeation of K(+) and Cl(-) ions. These findings are found to be robust to a choice of force-field parameters for ions (tested by Gromacs and Charmm force-fields for ions). What is more, a potassium ion is found to be able to permeate a membrane along an alternate, "water-defect-mediated" pathway without actual formation of a pore. The "water-defect-mediated" leakage involves formation of a single water defect only and is found to be at least one order of magnitude faster than the pore-mediated ion leakage.
我们采用了原子尺度的分子动力学模拟来研究无蛋白磷脂膜中通过瞬态水孔的离子泄漏。我们对含有氯化钠和氯化钾盐的水溶液中的磷脂膜的研究结果表明，瞬态水孔的形成以及随之而来的离子泄漏可以由跨膜离子电荷不平衡引发并驱动，这是活细胞的一个固有特征。如果这种梯度足够大，能够在膜上产生足够显著的电位差，这些过程就会发生。然后可以看到阳离子和阴离子通过水孔的运输；它消除了跨膜电位，显著减小了水孔的大小，并使水孔处于亚稳态，最终导致其封闭。发现离子运输对离子类型敏感。结果表明，尽管钠离子通过孔渗透时预计会遇到较低的势垒，但钠离子和氯离子以大致相同的比例透过膜。这是因为钠离子与磷脂膜的羰基区域以及形成孔“壁”的脂质头部基团有强烈相互作用，大大减缓了钠离子的渗透。相比之下，与氯离子相比，我们观察到磷脂膜对钾离子渗透具有明显的选择性：钾离子比钠离子大，与磷脂头部基团的相互作用较弱，因此这些相互作用无法弥补钾离子和氯离子渗透自由能垒的巨大差异。这些发现对于离子力场参数的选择具有鲁棒性（通过用于离子的Gromacs和Charmm力场进行测试）。此外，发现钾离子能够沿着一条交替的“水缺陷介导”途径渗透膜，而无需实际形成孔。“水缺陷介导”的泄漏仅涉及单个水缺陷的形成，并且发现其速度比孔介导的离子泄漏至少快一个数量级。
