The α7 nicotinic acetylcholine receptor is a homopentameric ion channel from the Cys-loop receptor superfamily targeted for psychiatric indications and inflammatory pain. Molecular dynamics studies of the receptor have focused on residue mobility and global conformational changes to address receptor function. However, a comparative analysis of α7 with its homologs that cannot trigger channel opening has not been made so far. To identify the residues involved in α7 activation, we ran triplicate 500-ns molecular dynamics simulations with an α7 extracellular domain homology model and two acetylcholine-binding protein homologs. We tested the effect of ligand binding and amino acid sequence on the structure and dynamics of the three proteins. We found that mobile regions identified based on root mean-square deviation and root mean-square fluctuation values are not always consistent among the individual α7 extracellular domain simulations. Comparison of the replica-average properties of the three proteins based on dynamic cross-correlation maps showed that ligand binding affects the coupling between the C-loop and the Cys-loop, vestibular loop, and β1-β2 loops. In addition, the main-immunogenic-region-like domain of α7 went through correlated motions with multiple domains of the receptor. These correlated motions were absent or diminished in α7 homologs, suggesting a unique role in α7 activation.

中文翻译：

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α7 nAChR 及其同系物动力学因素的计算分析

α7 烟碱乙酰胆碱受体是来自 Cys-loop 受体超家族的同型五聚体离子通道，用于治疗精神疾病和炎症性疼痛。受体的分子动力学研究集中在残基流动性和全局构象变化以解决受体功能。然而，迄今为止尚未对α7与其不能触发通道开放的同系物进行比较分析。为了鉴定参与 α7 激活的残基，我们使用 α7 细胞外结构域同源模型和两个乙酰胆碱结合蛋白同源物进行了三次重复的 500 ns 分子动力学模拟。我们测试了配体结合和氨基酸序列对三种蛋白质的结构和动力学的影响。我们发现基于均方根偏差和均方根波动值识别的移动区域在各个 α7 细胞外域模拟中并不总是一致的。基于动态互相关图比较三种蛋白质的复制平均特性表明配体结合影响 C 环和 Cys 环、前庭环和 β1-β2 环之间的耦合。此外，α7 的主要免疫原区样结构域与受体的多个结构域发生相关运动。这些相关的运动在 α7 同源物中不存在或减弱，表明在 α7 激活中具有独特的作用。基于动态互相关图比较三种蛋白质的复制平均特性表明配体结合影响 C 环和 Cys 环、前庭环和 β1-β2 环之间的耦合。此外，α7 的主要免疫原区样结构域与受体的多个结构域发生相关运动。这些相关的运动在 α7 同源物中不存在或减弱，表明在 α7 激活中具有独特的作用。基于动态互相关图比较三种蛋白质的复制平均特性表明配体结合影响 C 环和 Cys 环、前庭环和 β1-β2 环之间的耦合。此外，α7 的主要免疫原区样结构域与受体的多个结构域发生相关运动。这些相关的运动在 α7 同源物中不存在或减弱，表明在 α7 激活中具有独特的作用。