Exploring the gating mechanism in the ClC chloride channel via metadynamics
Exploring the gating mechanism in the ClC chloride channel via metadynamics
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DOI：
10.1016/j.jmb.2006.06.034
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发表时间：
2006-08-11
影响因子：
5.6
通讯作者：
Klein, Michael L.
中科院分区：
文献类型：
--
作者：
Gervasio, Francesco Luigi;Parrinello, Michele;Klein, Michael L.
计算机模拟已经被用来探索沙门氏菌血清型氯化鼠伤寒沙门氏菌通道(st-CLC)的门控机制。具体地说，最近开发的元动力学方法已经被用来构建自由能表面，作为孔内一个或两个氯离子的位置、关键E148残基的位置和质子化状态以及配位离子的水分子数量的函数。目前的计算证实了多离子机制，其中离子-推离子效应降低了氯离子转移的主要势垒。当考虑第二个阴离子时，在野生型通道中，氯通过E148窄区的势垒被计算为6kcal/mol，而与E148残基的质子化状态无关，这被证明只影响进入势垒。在E148A突变体中，这一屏障要低得多，达到3千卡/摩尔。这里报道的元动力学计算还表明，在到达周质溶液之前，氯离子必须克服由于两种不同的影响而产生的额外障碍，即它们的溶剂化壳的重排和位于αF螺旋末端的E148和G149残基的主干角度的翻转。(C)2006爱思唯尔有限公司。保留所有权利。
Computer simulations have been used to probe the gating mechanism in the Salmonella serovar typhimurium chloride channel (st-ClC). Specifically, the recently developed metadynamics methodology has been exploited to construct free energy surfaces as a function of the positions of either one or two chloride ions inside the pore, the position and protonation state of the key E148 residue, and the number of water molecules coordinating the translocating ions. The present calculations confirm the multi-ion mechanism in which an ion-push-ion effect lowers the main barriers to chloride ion translocation. When a second anion is taken into account, the barrier for chloride passage through the E148 narrow region is computed to be 6 kcal/mol in the wild-type channel, irrespective of the protonation state of the E148 residue, which is shown to only affect the entrance barrier. In the E148A mutant, this barrier is much lower, amounting to 3 kcal/mol. The metadynamics calculations reported herein also demonstrate that before reaching the periplasmic solution, chloride ions have to overcome an additional barrier arising from two different effects, namely the rearrangement of their solvation shell and a flip in the backbone angles of the residues E148 and G149, which reside at the end of the alpha F helix. (c) 2006 Elsevier Ltd. All rights reserved.