Department of Chemistry , Seoul National University , Seoul 08826 , Korea.
J Phys Chem B. 2019 Sep 19;123(37):7859-7868. doi: 10.1021/acs.jpcb.9b07195. Epub 2019 Sep 6.
Amyloid deposits of Aβ protein in neuronal cells are known to be a major symptom of Alzheimer's disease. In particular, Aβ shows relatively high toxicity among the different Aβ isoforms, and its toxicity is thought to be because of its structural features. Recent ssNMR and cryo-EM experiments identified that Aβ shows an S-shaped triple-β structure, in contrast to the previously suggested U-shaped β-arch structure. In order to associate the high toxicity of Aβ with its structural features, it is essential to explain the conformational stability and aggregation mechanisms of this triple-β motif. We utilized several different simulation methods, including extensive straight molecular dynamics simulation, steered molecular dynamics simulation, and replica-exchange molecular dynamics simulation. The S-shaped triple-β motif showed remarkable structural stability because of its complex residual interactions that form stable hydrophobic cores. The triple-β structure of Aβ is primarily made up of three β-sheet regions and two hydrophobic cores formed between β-sheet regions. Our analysis of β-sheet rupture patterns between adjacent chains showed that its two hydrophobic cores have different degrees of stability, indicating a lock phase mechanism. Our analysis of the docking pathway of monomeric Aβ to the fibril motif using REMD simulations showed that each of the three β-sheet sequences plays a distinct role in the docking process by changing their conformational features. Our results provide an understanding for the stability and consequent high toxicity of the triple-β structure Aβ.
细胞中 Aβ 蛋白的淀粉样沉积物是阿尔茨海默病的主要症状之一。特别是，Aβ 在不同的 Aβ 异构体中表现出相对较高的毒性，其毒性被认为与其结构特征有关。最近的 ssNMR 和 cryo-EM 实验表明，Aβ 呈现出 S 形的三-β 结构，与之前提出的 U 形 β-拱结构相反。为了将 Aβ 的高毒性与其结构特征联系起来，解释这种三-β 基序的构象稳定性和聚集机制至关重要。我们利用了几种不同的模拟方法，包括广泛的直驱分子动力学模拟、导向分子动力学模拟和复制交换分子动力学模拟。S 形三-β 基序由于其形成稳定疏水区的复杂残留相互作用而表现出显著的结构稳定性。Aβ 的三-β 结构主要由三个β-折叠区域和两个β-折叠区域之间形成的两个疏水区组成。我们对相邻链之间β-折叠断裂模式的分析表明，其两个疏水区的稳定性不同，表明存在锁相机制。我们使用 REMD 模拟对单体 Aβ 对接至原纤维基序的对接途径进行了分析，结果表明，三个β-折叠序列中的每一个都通过改变其构象特征在对接过程中发挥独特的作用。我们的结果为三-β 结构 Aβ 的稳定性和由此产生的高毒性提供了理解。
