An energy-efficient gating mechanism in the acetylcholine receptor channel suggested by molecular and Brownian dynamics
An energy-efficient gating mechanism in the acetylcholine receptor channel suggested by molecular and Brownian dynamics
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DOI：
10.1529/biophysj.105.067868
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发表时间：
2006-02-01
影响因子：
3.4
通讯作者：
Corry, B
中科院分区：
文献类型：
--
作者：
Corry, B
乙酰胆碱受体通过打开和关闭跨膜离子传导孔来介导神经和肌肉之间的电信号。分子和布朗动力学模拟被用来阐明的位置和机制的沟道门。四个单独的5 ns分子动力学模拟进行成像的通道，一个假设的开放结构，具有稍宽的孔和突变体结构，其中疏水残基的中心环被极性基团取代的结构。水被发现部分抽空的孔隙成像结构的分子模拟过程中，而离子面临着一个大的能量势垒，并不通过通道进行布朗动力学模拟。尽管包含穿过膜的无阻碍路径，但孔似乎处于闭合构型，因为通道中心的一系列疏水残基为水和离子提供了不利的家园。当通道稍微加宽时，水会涌入通道，离子的传导速度与在开放通道中实验测量的电流相当。孔保持离子可渗透性，只要孔内衬螺旋的细胞外末端被限制在假定的开放构型附近以模拟配体结合结构域的存在。用极性残基取代一些疏水残基降低了离子渗透的屏障，但不会导致显著的电流。该通道被假定为利用能量有效的门控机制，其中仅需要孔的疏水区域的微小构象变化来产生电导的宏观变化。
Acetylcholine receptors mediate electrical signaling between nerve and muscle by opening and closing a transmembrane ion conductive pore. Molecular and Brownian dynamics simulations are used to shed light on the location and mechanism of the channel gate. Four separate 5 ns molecular dynamics simulations are carried out on the imaged structure of the channel, a hypothetical open structure with a slightly wider pore and a mutant structure in which a central ring of hydrophobic residues is replaced by polar groups. Water is found to partially evacuate the pore during molecular simulations of the imaged structure, whereas ions face a large energy barrier and do not conduct through the channel in Brownian dynamics simulations. The pore appears to be in a closed configuration despite containing an unobstructed pathway across the membrane as a series of hydrophobic residues in the center of the channel provide an unfavorable home to water and ions. When the channel is widened slightly, water floods into the channel and ions conduct at a rate comparable to the currents measured experimentally in open channels. The pore remains permeable to ions provided the extracellular end of the pore-lining helix is restrained near the putative open configuration to mimic the presence of the ligand binding domain. Replacing some of the hydrophobic residues with polar ones decreases the barrier for ion permeation but does not result in significant currents. The channel is posited to utilize an energy efficient gating mechanism in which only minor conformational changes of the hydrophobic region of the pore are required to create macroscopic changes in conductance.