School of Chemistry and Chemical Engineering, University of Jinan, Jinan, 250022, People's Republic of China.
J Mol Model. 2024 Jun 28;30(7):233. doi: 10.1007/s00894-024-06032-w.
Existing researches confirmed that β amyloid (Aβ) has a high affinity for the α7 nicotinic acetylcholine receptor (α7nAChR), associating closely to Alzheimer's disease. The majority of related studies focused on the experimental reports on the neuroprotective role of Aβ fragment (Aβ), however, with a lack of investigation into the most suitable binding region and mechanism of action between Aβ fragment and α7nAChR. In the study, we employed four Aβ fragments Aβ, Aβ, Aβ, Aβ, and Aβ, of which the first three were confirmed to play neuroprotective roles upon directly binding, to interact with α7nAChR.
The protein-ligand docking server of CABS-DOCK was employed to obtain the α7nAChR-Aβ complexes. Only the top α7nAChR-Aβ complexes were used to perform all-atom GROMACS dynamics simulation in combination with Charmm36 force field, by which α7nAChR-Aβ interactions' dynamic behavior and specific locations of these different Aβ fragments were identified. MM-PBSA calculations were also done to estimate the binding free energies and the different contributions from the residues in the Aβ. Two distinct results for the first three and fourth Aβ fragments in binding site, strength, key residue, and orientation, account for why the fourth fails to play a neuroprotective role at the molecular level.
现有研究证实β淀粉样蛋白（Aβ）与α7 烟碱型乙酰胆碱受体（α7nAChR）具有高亲和力，与阿尔茨海默病密切相关。大多数相关研究集中在 Aβ 片段（Aβ）的神经保护作用的实验报告上，但缺乏对 Aβ 片段与 α7nAChR 之间最适宜结合区域和作用机制的研究。在本研究中，我们采用了四个 Aβ 片段 Aβ、Aβ、Aβ、Aβ 和 Aβ，其中前三个被证实通过直接结合发挥神经保护作用，与 α7nAChR 相互作用。
采用 CABS-DOCK 蛋白配体对接服务器获得 α7nAChR-Aβ 复合物。仅使用排名最高的 α7nAChR-Aβ 复合物，结合 Charmm36 力场进行全原子 GROMACS 动力学模拟，从而确定 α7nAChR-Aβ 相互作用的动态行为以及这些不同 Aβ 片段的特定位置。还进行了 MM-PBSA 计算，以估计结合自由能和 Aβ 中残基的不同贡献。前三个和第四个 Aβ 片段在结合位点、强度、关键残基和取向方面的两个截然不同的结果，解释了为什么第四个 Aβ 片段在分子水平上不能发挥神经保护作用。
