A computational study of the closed and open states of the influenza a M2 proton channel.
A computational study of the closed and open states of the influenza a M2 proton channel.
复制标题
DOI：
10.1529/biophysj.105.066647
复制
发表时间：
2005-10
影响因子：
3.4
通讯作者：
Yujie Wu;G. Voth
中科院分区：
文献类型：
--
作者：
Yujie Wu;G. Voth
在这项研究中，通过基于固态核磁共振限制的构象扫描，确定了流感M2离子通道闭合状态的His-37和Trp-41残基的四种可能的构象。在四种构象中，His-37残基可以是t-160或t60旋转异构体，而Trp-41可以是t-105或t90旋转异构体。通过密度泛函理论计算和分子动力学模拟进一步分析了这些构象，数据表明His-37残基最有可能采用t60旋转异构体，并且应该在δ-氮位点被单质子化，而Trp-41采用t90旋转异构体。这一结果与已发表的实验数据一致，并指出了一个简单的门控机制：在封闭状态下，His-37和Trp-41残基采用（t60，t90）构象，几乎堵塞了孔，由于空间位阻和去溶剂化效应，阻止非质子离子通过。此外，His-37四分体通过迫使其上方和下方的水分子采取相反的取向来中断孔隙水的连续氢键网络，从而增加了质子穿梭的阻塞。通过将His-37 chi 2角度从60度旋转到0度，可以容易地打开通道。这种开放的结构允许孔隙水渗透收缩区域，并形成连续的水线供质子穿梭通过，同时仍然足够窄以排除其他离子。
In this study, four possible conformations of the His-37 and Trp-41 residues for the closed state of the influenza M2 ion channel were identified by a conformation scan based on a solid-state NMR restraint. In the four conformations, the His-37 residue can be of either the t-160 or t60 rotamer, whereas Trp-41 can be of either the t-105 or t90 rotamer. These conformations were further analyzed by density functional theory calculations and molecular dynamics simulations, and the data indicate that the His-37 residue most likely adopts the t60 rotamer and should be monoprotonated at the delta-nitrogen site, whereas Trp-41 adopts the t90 rotamer. This result is consistent with published experimental data and points to a simple gating mechanism: in the closed state, the His-37 and Trp-41 residues adopt the (t60, t90) conformation, which nearly occludes the pore, preventing nonproton ions from passing through due to the steric and desolvation effects. Moreover, the His-37 tetrad interrupts the otherwise continuous hydrogen-bonding network of the pore water by forcing the water molecules above and below it to adopt opposite orientations, thus adding to the blockage of proton shuttling. The channel can be easily opened by rotating the His-37 chi2 angle from 60 to 0 degrees . This open structure allows pore water to penetrate the constrictive region and to form a continuous water wire for protons to shuttle through, while being still narrow enough to exclude other ions.