Bioinformatik Institut für Biochemie Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstr. 17, 91054, Erlangen, Germany.
J Mol Model. 2019 Jan 12;25(2):37. doi: 10.1007/s00894-018-3920-4.
Alzheimer's disease is characterized by the aggregation of Amyloid-β (Aβ) peptide into oligomers, fibrils and plaques. Many factors influencing this process as well as the stability of the various Aβ aggregates are known to date, and include the concentration and type of metal ions. Most experimental and theoretical studies have concentrated on heavy metal ions, like Fe, Zn, or Cu, while the smaller alkali ions Li, Na, and K have not gained much attention notwithstanding their role and ubiquity in physiological environments. In this work, we applied atomistic molecular dynamics simulations to investigate the potential role of these alkali ions in stabilizing fibrillar Aβ oligomers of different size and topology, i.e., single and double filament systems comprising 3-24 peptide chains per filament. We find a pronounced difference on the molecular level in the interaction behavior with free carboxylate groups of the Aβ oligomer: Li forms stable bridged interactions, whereas K interacts more transiently and lacks bridging. The behavior of Na is in between, so that this ion-protein interaction obeys the renowned Hofmeister series. These differences are also reflected in the ability of the alkali ions to stabilize the oligomer secondary structure. The stabilizing effect is most pronounced for the smaller fibrillar oligomers, suggesting that the type of alkali ion critically affects the initial stages of fibril formation. Our findings thus offer a molecular explanation for the observation that the polymorphisms of Aβ fibril structures are caused by differences in the surrounding ionic environment. Graphical abstract Influence of alkali ions on the structure and stability of fibrillar amyloid-β oligomers.
阿尔茨海默病的特征是淀粉样β（Aβ）肽聚集形成寡聚物、原纤维和斑块。迄今为止，许多影响这一过程的因素以及各种 Aβ 聚集物的稳定性都已被了解，其中包括金属离子的浓度和类型。大多数实验和理论研究都集中在重金属离子上，如 Fe、Zn 或 Cu，而较小的碱金属离子 Li、Na 和 K 尽管在生理环境中具有重要作用且无处不在，但却没有得到太多关注。在这项工作中，我们应用原子分子动力学模拟来研究这些碱金属离子在稳定不同大小和拓扑结构的纤维状 Aβ 寡聚物中的潜在作用，即由 3-24 条肽链组成的单丝和双丝系统。我们发现，在与 Aβ 寡聚物游离羧基基团的相互作用行为方面，存在明显的分子水平差异：Li 形成稳定的桥接相互作用，而 K 则表现出更短暂的相互作用且缺乏桥接。Na 的行为介于两者之间，因此这种离子-蛋白质相互作用符合著名的 Hofmeister 序列。这些差异也反映在碱金属离子稳定寡聚物二级结构的能力上。对于较小的纤维状寡聚物，这种稳定作用最为明显，这表明碱金属离子的类型对纤维形成的初始阶段有重大影响。因此，我们的发现为观察到 Aβ 纤维结构的多态性是由周围离子环境的差异引起的这一现象提供了分子解释。
