Molecular Dynamics Simulations of Ion Selectivity in a Claudin-15 Paracellular Channel
Molecular Dynamics Simulations of Ion Selectivity in a Claudin-15 Paracellular Channel
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DOI：
10.1021/acs.jpcb.8b06484
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发表时间：
2018-12-06
影响因子：
3.3
通讯作者：
Maragliano, Luca
中科院分区：
文献类型：
--
作者：
Alberini, Giulio;Benfenati, Fabio;Maragliano, Luca
密蛋白是组织特异性跨膜蛋白，能够在两个细胞之间形成连接并调节生理溶质平行于细胞壁的流动，即细胞旁运输。 Claudin-15 在肠道中高度表达，形成有效的 Na+ 通道和 Cl(- ) 屏障。然而，这些生物复合物的分子细节仍不清楚。在这里，使用双层和显式溶剂中的全原子分子动力学模拟研究了 Claudin-15 旁细胞通道的精细结构模型内 Na+、K+ 和 Cl- 离子的渗透过程。使用伞式采样 (US) 模拟计算的一维平均力势 (PMF) 曲线表明，该通道允许两种生理阳离子通过，同时排除氯离子。这些特征是由几个酸性残基的作用产生的，特别是位于孔最窄区域的 D55 残基环，与阳离子的能量最小值和氯离子的峰值相对应。我们还使用 Voronoi 棋盘格里程碑方法来获得额外的 PMF 剖面和三个离子的渗透时间尺度。具有里程碑意义的 PMF 与美国获得的结果非常吻合，并且速率计算表明氯离子的通过速度几乎比钠慢 30 倍。我们的结果与已知的claudin-15调节紧密连接选择性的能力以及通过实验确定的酸性残基的作用一致。这进一步验证了我们的结构模型，并提供了对细胞旁通道中离子传输的原子细节的见解，这些细节可以由其他基于密蛋白的架构共享。
Claudins are tissue-specific transmembrane proteins able to form junctions between two cells and regulate the flow of physiological solutes parallel to the cell walls, that is, the paracellular transport. Claudin-15 is highly expressed in the intestine where it forms efficient Na+ channels and Cl(- )barriers. However, the molecular details of these biological complexes are still unclear. Here, the permeation process of Na+, K+, and Cl- ions inside a refined structural model of a claudin-15 paracellular channel is investigated using all-atom molecular dynamics simulations in a double-bilayer and explicit solvent. One-dimensional potential of mean force (PMF) profiles, calculated using umbrella sampling (US) simulations, show that the channel allows the passage of the two physiological cations while excluding chloride. These features are generated by the action of several acidic residues, in particular the ring of D55 residues which is located at the narrowest region of the pore, in correspondence with the energy minimum for cations and the peak for chloride. We also used the Voronoi-tessellated milestoning method to obtain additional PMF profiles and the permeation timescale of the three ions. The milestoning PMFs agree well with those obtained by US, and the rate calculation reveals that the passage of chloride is almost 30 times slower than that of sodium. Our results are consistent with the known ability of claudin-15 to regulate tight junction selectivity and with the experimentally determined role of the acidic residues. This further validates our structural model and provides insights into the atomistic details of ion transport in paracellular channels that could be shared by other claudin-based architectures.