Enhancement of Proton Conductance by Mutations of the Selectivity Filter of Aquaporin-1
Enhancement of Proton Conductance by Mutations of the Selectivity Filter of Aquaporin-1
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DOI：
10.1016/j.jmb.2011.01.036
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发表时间：
2011-04-08
影响因子：
5.6
通讯作者：
Voth, Gregory A.
中科院分区：
文献类型：
--
作者：
Li, Hui;Chen, Hanning;Voth, Gregory A.
野生型水通道蛋白-1(AQP1)的阳离子渗透被认为与ASN-Pro-Ala(NPA)区域和芳香/精氨酸选择性过滤(SF)结构域有关。以前的工作表明，NPA区域有助于阻止质子的渗透，因为蛋白质主干集体大偶极创造了一个有利于方向不连续的通道、氢键水链和巨大的静电屏障的环境。SF结构域通过空间限制机制和直接静电相互作用对质子渗透势垒起到了作用。为了进一步探索这些不同的影响，计算预测了各种阳离子通过AQP1-R195V和AQP1-R195S突变体渗透的自由能垒和最大阳离子电导。所研究的阳离子包括利用格罗特休斯穿梭机制的水合过剩质子，一个没有格洛特斯穿梭的经典电荷局域氢阳离子模型，以及一个钠阳离子。用一种特殊的多态分子动力学方法模拟了水合过剩质子，包括对质子穿梭和电荷缺陷离域进行适当的物理处理。由于SF区水结构的改变，两个AQP1突变体都表现出令人惊讶的合作效应，导致NPA区质子渗透的自由能势垒降低，其中AQP1-R195S的电导高于AQP1-R195V。理论预测在野生型AQP1和突变体的Xeno Pus卵母细胞中得到了实验验证。综合结果表明，SF结构域是一种特殊的结构，它已经进化到阻止质子在水通道蛋白中的渗透。(C)2011爱思唯尔有限公司。保留所有权利。
Prevention of cation permeation in wild-type aquaporin-1 (AQP1) is believed to be associated with the Asn-Pro-Ala (NPA) region and the aromatic/arginine selectivity filter (SF) domain. Previous work has suggested that the NPA region helps to impede proton permeation due to the protein backbone collective macrodipoles that create an environment favoring a directionally discontinuous channel hydrogen-bonded water chain and a large electrostatic barrier. The SF domain contributes to the proton permeation barrier by a spatial restriction mechanism and direct electrostatic interactions. To further explore these various effects, the free-energy barriers and the maximum cation conductance for the permeation of various cations through the AQP1-R195V and AQP1-R195S mutants are predicted computationally. The cations studied included the hydrated excess proton that utilizes the Grotthuss shuttling mechanism, a model "classical" charge localized hydronium cation that exhibits no Grotthuss shuttling, and a sodium cation. The hydrated excess proton was simulated using a specialized multi-state molecular dynamics method including a proper physical treatment of the proton shuttling and charge defect delocalization. Both AQP1 mutants exhibit a surprising cooperative effect leading to a reduction in the free-energy barrier for proton permeation around the NPA region due to altered water configurations in the SF region, with AQP1-R195S having a higher conductance than AQP1-R195V. The theoretical predictions are experimentally confirmed in wild-type AQP1 and the mutants expressed in Xeno pus oocytes. The combined results suggest that the SF domain is a specialized structure that has evolved to impede proton permeation in aquaporins. (C) 2011 Elsevier Ltd. All rights reserved.