Qu Liang, Fudo Satoshi, Matsuzaki Katsumi, Hoshino Tyuji
Graduate School of Pharmaceutical Sciences, Chiba University.
Graduate School of Pharmaceutical Sciences, Kyoto University.
Chem Pharm Bull (Tokyo). 2019;67(9):959-965. doi: 10.1248/cpb.c19-00171.
Fibrillated aggregation of amyloid β (Aβ) peptides is a potential factor causing toxic amyloid deposition in neurodegenerative diseases. A toxic fibril formation of Aβ is known to be enhanced on the ganglioside-rich lipid membrane containing some amounts of cholesterol and sphingomyelin. This ganglioside-rich membrane is supposed to provide a hydrophobic environment that promotes the formation of Aβ fibrils. Molecular dynamics simulations were carried out to investigate the structure of Aβ complex in the hydrophobic solution composed of dioxane and water molecules. The Aβ conformation was contrasted to that in the aqueous condition by executing multiple computational trials with the calculation models containing one, four, or six Aβ peptides. The conformation was also compared between the calculations with the 42-mer (Aβ) and 40-mer (Aβ) peptides. The simulations for Aβ demonstrated that Aβ peptides had a tendency to stretch out in the hydrophobic environment. In contrast, Aβ peptides were closely packed in the aqueous solution, and the motions of Aβ peptides were suppressed significantly. The N-terminal polar domains of Aβ peptides tended to be positioned at the inside of the Aβ complex in the hydrophobic environment, which supported the C-terminal domains in expanding outward for inter-molecular interaction. Since Aβ peptides were not tightly packed in the hydrophobic environment, the total surface area of the Aβ complex in the hydrophobic solution was larger than that in the aqueous one. The simulation for Aβ peptides also showed a difference between the hydrophobic and aqueous solutions. The difference was compatible with the results of Aβ in the structure of the Aβ complex, while the C-terminal outward expansion was not so distinct as Aβ peptides.
淀粉样β（Aβ）肽的原纤维聚集是导致神经退行性疾病中有毒淀粉样沉积的一个潜在因素。已知在富含神经节苷脂且含有一定量胆固醇和鞘磷脂的脂质膜上，Aβ的有毒原纤维形成会增强。这种富含神经节苷脂的膜被认为提供了一个促进Aβ原纤维形成的疏水环境。进行了分子动力学模拟，以研究在由二氧六环和水分子组成的疏水溶液中Aβ复合物的结构。通过使用包含一个、四个或六个Aβ肽的计算模型进行多次计算试验，将Aβ的构象与在水性条件下的构象进行对比。还比较了42聚体（Aβ）和40聚体（Aβ）肽计算结果之间的构象。对Aβ的模拟表明，Aβ肽在疏水环境中有伸展的趋势。相比之下，Aβ肽在水溶液中紧密堆积，且Aβ肽的运动受到显著抑制。在疏水环境中，Aβ肽的N端极性结构域倾向于位于Aβ复合物内部，这有助于C端结构域向外扩展以进行分子间相互作用。由于Aβ肽在疏水环境中没有紧密堆积，因此疏水溶液中Aβ复合物的总表面积大于水溶液中的总表面积。对Aβ肽的模拟还显示了疏水和水溶液之间的差异。该差异与Aβ复合物结构中Aβ的结果一致，而C端向外扩展不如Aβ肽那么明显。
