Corry Ben
Chemistry, School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, Crawley, WA 6009, Australia.
Biophys J. 2006 Feb 1;90(3):799-810. doi: 10.1529/biophysj.105.067868. Epub 2005 Nov 11.
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.
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与肌肉之间的电信号传递。分子动力学模拟和布朗动力学模拟被用于阐明通道门的位置和机制。对通道的成像结构、一种孔径稍宽的假设开放结构以及一种突变结构(其中疏水残基的中央环被极性基团取代)进行了四个独立的5纳秒分子动力学模拟。在成像结构的分子模拟过程中,发现水部分地从孔中排出,而在布朗动力学模拟中离子面临很大的能量障碍,无法通过通道传导。尽管通道中存在一条穿过膜的无障碍通道,但由于通道中心的一系列疏水残基为水和离子提供了不利的环境,孔似乎处于关闭状态。当通道稍微变宽时,水涌入通道,离子传导速率与在开放通道中实验测量的电流相当。只要孔内衬螺旋的细胞外端被限制在假定的开放构象附近以模拟配体结合域的存在,孔就仍然对离子具有通透性。用极性残基取代一些疏水残基会降低离子渗透的障碍,但不会产生显著的电流。推测该通道利用一种节能的门控机制,其中只需孔的疏水区域发生微小的构象变化就能在电导率上产生宏观变化。