Exploring transmembrane transport through α-hemolysin with grid-steered molecular dynamics
Exploring transmembrane transport through α-hemolysin with grid-steered molecular dynamics
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DOI：
10.1063/1.2770738
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发表时间：
2007-09-28
影响因子：
4.4
通讯作者：
Aksimentiev, Aleksei
中科院分区：
文献类型：
--
作者：
Wells, David B.;Abramkina, Volha;Aksimentiev, Aleksei
生物分子跨越细胞边界的运输是细胞功能的核心。虽然许多膜通道的结构是已知的，但渗透机制只对少数几个已知。分子动力学（MD）是一种能够在原子水平上准确描述渗透事件的计算方法，这是理解传输机制所必需的。然而，由于该方法可获得的时间尺度相对较短，因此它的实用性有限。在这里，我们提出了一种全原子模拟大溶质通过膜通道的电场驱动输运的方法，该方法可以在几十纳秒内提供渗透事件的真实描述，而传统的MD模拟需要毫秒。在这种方法中，首先从全原子MD模拟中确定跨膜偏压下膜通道中静电势的平均分布。这个静电势，定义在一个网格上，随后应用于带电的溶质，以引导其渗透通过膜通道。我们应用这种方法来研究DNA链、DNA发夹和α -螺旋肽通过α溶血素的渗透。为了测试该方法的准确性，我们计算了具有不同序列和全局方向的DNA链的相对渗透率。实验结果表明，G-SMD模拟结果与实验结果吻合较好。
The transport of biomolecules across cell boundaries is central to cellular function. While structures of many membrane channels are known, the permeation mechanism is known only for a select few. Molecular dynamics (MD) is a computational method that can provide an accurate description of permeation events at the atomic level, which is required for understanding the transport mechanism. However, due to the relatively short time scales accessible to this method, it is of limited utility. Here, we present a method for all-atom simulation of electric field-driven transport of large solutes through membrane channels, which in tens of nanoseconds can provide a realistic account of a permeation event that would require a millisecond simulation using conventional MD. In this method, the average distribution of the electrostatic potential in a membrane channel under a transmembrane bias of interest is determined first from an all-atom MD simulation. This electrostatic potential, defined on a grid, is subsequently applied to a charged solute to steer its permeation through the membrane channel. We apply this method to investigate permeation of DNA strands, DNA hairpins, and alpha-helical peptides through alpha-hemolysin. To test the accuracy of the method, we computed the relative permeation rates of DNA strands having different sequences and global orientations. The results of the G-SMD simulations were found to be in good agreement in experiment.