Sansom M S, Adcock C, Smith G R
Laboratory of Molecular Biophysics, University of Oxford, United Kingdom.
J Struct Biol. 1998;121(2):246-62. doi: 10.1006/jsbi.1997.3950.
Molecular dynamics simulations with experimentally derived restraints have been used to develop atomic models of M2 helix bundles forming the pore-lining domains of the nicotinic acetylcholine receptor and related ligand-gated ion channels. M2 helix bundles have been used in microscopic simulations of the dynamics and energetics of water and ions within an ion channel. Translational and rotational motion of water are restricted within the pore, and water dipoles are aligned relative to the pore axis by the surrounding helix dipoles. Potential energy profiles for translation of a Na+ ion along the pore suggest that the protein and water components of the interaction energy exert an opposing effect on the ion, resulting in a relatively flat profile which favors cation permeation. Empirical conductance calculations based on a pore radius profile suggest that the M2 helix model is consistent with a single channel conductance of ca. 50 pS. Continuum electrostatics calculations indicate that a ring of glutamate residues at the cytoplasmic mouth of the alpha 7 nicotinic receptor M2 helix bundle may not be fully ionized. A simplified model of the remainder of the channel protein when added to the M2 helix bundle plays a significant role in enhancing the ion selectivity of the channel.
利用具有实验推导约束条件的分子动力学模拟，构建了形成烟碱型乙酰胆碱受体及相关配体门控离子通道孔道内衬结构域的M2螺旋束的原子模型。M2螺旋束已被用于离子通道内水和离子动力学及能量学的微观模拟。水的平移和旋转运动在孔道内受到限制，并且水偶极子通过周围的螺旋偶极子相对于孔道轴排列。Na+离子沿孔道平移的势能分布表明，相互作用能的蛋白质和水成分对离子产生相反的作用，导致相对平坦的分布，有利于阳离子渗透。基于孔道半径分布的经验电导计算表明，M2螺旋模型与约50 pS的单通道电导一致。连续介质静电计算表明，α7烟碱型受体M2螺旋束胞质口处的谷氨酸残基环可能未完全电离。通道蛋白其余部分的简化模型添加到M2螺旋束中时，在增强通道的离子选择性方面发挥了重要作用。
