Vahed Majid, Neya Saburo, Matsuzaki Katsumi, Hoshino Tyuji
Graduate School of Pharmaceutical Sciences, Chiba University.
Graduate School of Pharmaceutical Sciences, Kyoto University.
Chem Pharm Bull (Tokyo). 2018;66(2):170-177. doi: 10.1248/cpb.c17-00740.
Aggregation and complex formation of amyloid beta (Aβ) peptides on a neuronal cell membrane is a hallmark of neuro-disturbance diseases. In this work, we performed molecular dynamics (MD) simulations to investigate the initial stage of interactions of multiple Aβ peptides on a GM1 ganglioside-containing membrane that mimics a micro-domain on the neuronal cell surface. Conformational changes of Aβs due to adhesion on the membrane and subsequent molecular interactions among the Aβs were monitored. It was suggested from results of the two 1.0 µs simulation trials that stable complexes of Aβ peptides were not rapidly generated but that a steady binding of two Aβs was gradually formed. Observation of two Aβs that will be a complex with steady binding revealed that one Aβ was bound to the membrane surface, while the other was attached to the first one without strong contact with the membrane. The motion of the first one was restricted and its conformational change was limited, with the basic side-chains of Arg5 and Lys28 working as anchors to hold the Aβ helix region on the membrane. In contrast, the second one had high flexibility and showed diversity in its conformation. The second Aβ can search for an energetically favorable binding position on the first one. A parallel β-sheet structure was formed between the C-terminal sides of the two Aβs. Ala30 was critically important to lead the stable β-sheet conformation at the C-terminal hydrophobic domains of Aβs. In the N-terminal sides, helix structures were kept in both Aβs.
淀粉样β（Aβ）肽在神经元细胞膜上的聚集和复合物形成是神经紊乱疾病的一个标志。在这项工作中，我们进行了分子动力学（MD）模拟，以研究多个Aβ肽在含GM1神经节苷脂的膜上的相互作用初始阶段，该膜模拟了神经元细胞表面的微结构域。监测了由于Aβ肽粘附在膜上以及随后Aβ肽之间的分子相互作用而导致的Aβ肽构象变化。两次1.0微秒模拟试验的结果表明，Aβ肽的稳定复合物不是迅速形成的，而是两个Aβ肽逐渐形成稳定结合。对两个将形成稳定结合复合物的Aβ肽的观察表明，一个Aβ肽与膜表面结合，而另一个则附着在第一个Aβ肽上，与膜没有强烈接触。第一个Aβ肽的运动受到限制，其构象变化有限，Arg5和Lys28的碱性侧链作为锚将Aβ肽的螺旋区域固定在膜上。相比之下，第二个Aβ肽具有高灵活性，其构象表现出多样性。第二个Aβ肽可以在第一个Aβ肽上寻找能量上有利的结合位置。两个Aβ肽的C末端之间形成了平行β-折叠结构。Ala30对于在Aβ肽的C末端疏水结构域引导稳定的β-折叠构象至关重要。在N末端，两个Aβ肽均保持螺旋结构。
