Aquaporin-2 plays a vital role in the human kidney as a water passage channel. Any disorder with its function can cause water imbalance and consequently disease in humans, especially nephrogenic diabetes insipidus (NDI). For this reason, an accurate understanding of its performance can be useful for therapeutic purposes. In this article, we investigate the gating mechanism induced by spontaneous fluctuations in aquaporin-2's (AQP2) channels in the palmitoyl-oleoyl-phosphatidyl-ethanolamine lipid bilayer by molecular dynamics. Our results show that the selectivity filter (SF) in AQP2 is also a gating site depending on the side-chain conformation of His172. The important role of His172 in modulating the wide and narrow conformations has been further investigated by the simulation of the H172G mutant. The osmotic permeability values of all four monomers are in the range of wide state and the average is very close to that of the wide channel formed by wild-type AQP2. Moreover, by calculating the osmotic permeability and the potential of mean force of each of the AQP2 monomers for wide/narrow states of the SF, it is seen that the SF at its narrow conformation can induce a much larger energy barrier for water molecules permeation, hindering the transport of water molecules remarkably. The reason for the discrepancy among osmotic permeabilities of different monomers of aquaporins is revealed by investigating the osmotic permeability of each monomer through the wide/narrow states of their SF.

中文翻译：

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用分子动力学模拟研究水通道蛋白 2 门控机制

Aquaporin-2 作为水通道在人体肾脏中起着至关重要的作用。任何具有其功能的疾病都会导致水分失衡，从而导致人类疾病，尤其是肾源性尿崩症 (NDI)。因此，对其性能的准确了解可用于治疗目的。在本文中，我们通过分子动力学研究了棕榈酰-油酰-磷脂酰-乙醇胺脂质双层中水通道蛋白-2 (AQP2) 通道的自发波动引起的门控机制。我们的结果表明，AQP2 中的选择性过滤器 (SF) 也是一个门控位点，这取决于 His172 的侧链构象。通过模拟 H172G 突变体，进一步研究了 His172 在调节宽窄构象中的重要作用。所有四种单体的渗透率值都在宽态范围内，平均值非常接近野生型AQP2形成的宽通道。此外，通过计算每个 AQP2 单体在 SF 的宽/窄状态下的渗透渗透率和平均力的潜力，可以看出窄构象的 SF 可以诱导更大的水分子渗透能垒，显着阻碍水分子的运输。通过研究每个单体在其 SF 的宽/窄状态下的渗透渗透率，揭示了水通道蛋白不同单体渗透渗透率差异的原因。通过计算每个 AQP2 单体在 SF 的宽/窄状态下的渗透渗透率和平均力的潜力，可以看出窄构象的 SF 可以诱导更大的水分子渗透能垒，阻碍水分子的传输显着。通过研究每个单体在其 SF 的宽/窄状态下的渗透渗透率，揭示了水通道蛋白不同单体渗透渗透率差异的原因。通过计算每个 AQP2 单体在 SF 的宽/窄状态下的渗透渗透率和平均力的潜力，可以看出窄构象的 SF 可以诱导更大的水分子渗透能垒，阻碍水分子的传输显着。通过研究每个单体在其 SF 的宽/窄状态下的渗透渗透率，揭示了水通道蛋白不同单体渗透渗透率差异的原因。