Graduate School of Pharmaceutical Sciences , Chiba University , Inohana 1-8-1 , Chuo-ku, Chiba 260-8675 , Japan.
Graduate School of Pharmaceutical Sciences , Kyoto University , Sakyo-ku, Kyoto 606-8501 , Japan.
J Phys Chem B. 2018 Apr 12;122(14):3771-3781. doi: 10.1021/acs.jpcb.8b00139. Epub 2018 Mar 23.
The interaction of amyloid beta (Aβ) peptides with the cell membrane is one of the factors enhancing Aβ aggregation, which is closely related to neurodegenerative disease. In this work, we performed molecular dynamics (MD) simulation to investigate the initial stage of adhesion of Aβ to a GM1 ganglioside-containing membrane. Conformational change of Aβ due to interaction with the membrane was monitored and compared with that of Aβ observed in the previous study. Multiple computational trials were executed to analyze the probability of Aβ binding using a calculation model consisting of a GM1-containing mixed lipid membrane, a water layer, ions, and Aβ. A single long-time MD simulation was also carried out. It was suggested from the simulation that a cluster of sialic acids of GM1 head groups often caught the side chain of His13 or His14 of Aβ in the early stage of the MD simulations. Afterward, the main chain of Leu34 formed many hydrogen bonds with gangliosides. These residues cooperatively work for Aβ to be held on the lipid membrane. It is notable that Aβ was observed to be deeply inserted into the head group region of the lipid membrane in some computational trials. In the insertion, Aβ occasionally formed a hydrogen bond with sphingomyelin. The difference in the secondary structure between Aβ and Aβ was an important factor for Aβ to be deeply inserted into the membrane.
淀粉样蛋白β（Aβ）肽与细胞膜的相互作用是增强 Aβ聚集的因素之一，这与神经退行性疾病密切相关。在这项工作中，我们进行了分子动力学（MD）模拟，以研究 Aβ与含有 GM1 神经节苷脂的膜初始粘附的阶段。监测了 Aβ与膜相互作用引起的构象变化，并将其与之前研究中观察到的 Aβ进行了比较。使用包含 GM1 混合脂质膜、水层、离子和 Aβ的计算模型，执行了多次计算试验以分析 Aβ结合的概率。还进行了单次长时间 MD 模拟。模拟表明，在 MD 模拟的早期，GM1 头部基团的唾液酸簇经常抓住 Aβ的 His13 或 His14 侧链。此后，Leu34 的主链与神经节苷脂形成了许多氢键。这些残基共同作用使 Aβ固定在脂质膜上。值得注意的是，在一些计算试验中观察到 Aβ被深深地插入到脂质膜的头部基团区域。在插入过程中，Aβ偶尔与鞘磷脂形成氢键。Aβ与 Aβ之间的二级结构差异是 Aβ被深深地插入膜中的重要因素。
