The nicotinic acetylcholine receptor: from molecular model to single-channel conductance
The nicotinic acetylcholine receptor: from molecular model to single-channel conductance
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DOI：
10.1007/s002490050248
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发表时间：
2000-01-01
影响因子：
2
通讯作者：
Sansom, MSP
中科院分区：
文献类型：
--
作者：
Adcock, C;Smith, GR;Sansom, MSP
烟碱乙酰胆碱受体（nAChR）是典型的配体门控离子通道。的alpha 7 homopentameric nAChR的模型中描述的孔内衬M2螺旋束原子化处理和分子的其余部分被视为一个“低分辨率”的圆柱体。圆柱体上的表面电荷来源于氨基酸序列中带电氨基酸的分布（不包括M2片段）。基于该模型推导的静电势分布，利用一维Poisson-Nernst-Planck方程计算了单通道电流/电压曲线。预测的单通道电导是三倍高（约。150 pS）比实验测得的，和预测的离子选择性同意与观察到的阳离子选择性nAChR。分子动力学（MD）模拟用于估计通道内的水分子的自扩散系数（D）。在孔隙的最西部区域，D减小约。是散装水的三倍。假设离子的扩散与水的扩散成比例，这产生了单通道电导的修正预测（约2.5倍）。50 pS）与实验值吻合较好。我们的结论是，结合原子（MD）和连续静电计算是一个很有前途的方法来弥合离子通道的结构和生理之间的差距。
The nicotinic acetylcholine receptor (nAChR) is the archetypal ligand-gated ion channel. A model of the alpha7 homopentameric nAChR is described in which the pore-lining M2 helix bundle is treated atomistically and the remainder of the molecule is treated as a "low resolution" cylinder. The surface charge on the cylinder is derived from the distribution of charged amino acids in the amino acid sequence (excluding the M2 segments). This model is explored in terms of its predicted single-channel properties, Based on electrostatic potential profiles derived from the model, the one-dimensional Poisson-Nernst-Planck equation is used to calculate single-channel current/voltage curves. The predicted single-channel conductance is three times higher (ca. 150 pS) than that measured experimentally, and the predicted ion selectivity agrees with the observed cation selectivity of nAChR. Molecular dynamics (MD) simulations are used to estimate the self-diffusion coefficients (D) of water molecules within the channel. In the narrowest region of the pore, D is reduced ca. threefold relative to that of bulk water. Assuming that the diffusion of ions scales with that of water, this yields a revised prediction of the single-channel conductance (ca. 50 pS) in good agreement with the experimental value. We conclude that combining atomistic (MD) and continuum electrostatics calculations is a promising approach to bridging the gap between structure and physiology of ion channels.