Proton transport Behavior through the influenza a M2 channel: Insights from molecular simulation
Proton transport Behavior through the influenza a M2 channel: Insights from molecular simulation
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DOI：
10.1529/biophysj.107.105742
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发表时间：
2007-11-01
影响因子：
3.4
通讯作者：
Voth, Gregory A.
中科院分区：
文献类型：
--
作者：
Chen, Hanning;Wu, Yujie;Voth, Gregory A.
利用多态经验价键（MS - EVB）方法，通过经典分子动力学研究了甲型流感病毒M2跨膜通道在二肉豆蔻酰磷脂酰胆碱双层膜中的结构特性，包括质子门控His - 37四联体的四种质子化状态，以及它们对这种低pH激活、高质子选择性通道的质子转运的影响。由MS - EVB模拟数据结合泊松 - 能斯特 - 普朗克理论计算得到的过剩质子渗透自由能曲线和最大离子电导表明，通过His - 37四联体显著的侧链构象变化，三重质子化的His - 37状态是最有可能的开放状态。与实验值6 pS相比，所提出的M2这种开放状态计算得到的质子渗透自由能垒为7 kcal/mol，最大电导为53 pS。相比之下，计算得到的Na⁺最大电导要低四个数量级，这与实验观察到的质子选择性合理一致。根据介电连续体理论，激活通道开放的pH值估计为5.5，这也与实验结果相符。这项研究进一步揭示，Ala - 29残基区域是抗流感药物金刚烷胺（AMT）的主要结合位点，可能是因为该区域相对宽敞且具有疏水性。计算表明，由于通道结合的AMT附近过剩质子的显著去水代价，AMT的存在使质子电导降低了99.8%。
The structural properties of the influenza A virus M2 transmembrane channel in dimyristoylphosphatidylcholine bilayer for each of the four protonation states of the proton-gating His-37 tetrad and their effects on proton transport for this low-pH activated, highly proton-selective channel are studied by classical molecular dynamics with the multistate empirical valencebond (MS-EVB) methodology. The excess proton permeation free energy pro. le and maximum ion conductance calculated from the MS-EVB simulation data combined with the Poisson-Nernst-Planck theory indicates that the triply protonated His-37 state is the most likely open state via a significant side-chain conformational change of the His-37 tetrad. This proposed open state of M2 has a calculated proton permeation free energy barrier of 7 kcal/mol and a maximum conductance of 53 pS compared to the experimental value of 6 pS. By contrast, the maximum conductance for Na+ is calculated to be four orders of magnitude lower, in reasonable agreement with the experimentally observed proton selectivity. The pH value to activate the channel opening is estimated to be 5.5 from dielectric continuum theory, which is also consistent with experimental results. This study further reveals that the Ala-29 residue region is the primary binding site for the antiflu drug amantadine (AMT), probably because that domain is relatively spacious and hydrophobic. The presence of AMT is calculated to reduce the proton conductance by 99.8% due to a significant dehydration penalty of the excess proton in the vicinity of the channel-bound AMT.