Molecular interactions of Alzheimer amyloid-β oligomers with neutral and negatively charged lipid bilayers.
Molecular interactions of Alzheimer amyloid-β oligomers with neutral and negatively charged lipid bilayers.
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DOI：
10.1039/c3cp44448a
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发表时间：
2013-06-21
期刊：
影响因子：
--
通讯作者：
Zheng J
中科院分区：
文献类型：
--
作者：
Yu X;Wang Q;Pan Q;Zhou F;Zheng J
p3 (Aβ17-42) 肽与细胞膜的相互作用对于了解与阿尔茨海默病 (AD) 相关的淀粉样蛋白毒性至关重要。这种 p3 膜相互作用被认为会诱导膜通透性和完整性的破坏，但 p3 聚集体（特别是小的 p3 寡聚物）如何诱导不依赖于受体的膜破坏的确切机制尚未完全了解。在这里，我们使用显式溶剂分子动力学 (MD) 模拟研究了 p3 五聚体与由纯两性离子 POPC（棕榈酰油酰磷脂酰胆碱）和混合阴离子 POPC/POPG（棕榈酰油酰磷脂酰甘油）（3:1）脂质组成的脂质双层的吸附、取向和表面相互作用。 MD模拟结果表明，p3五聚体与混合POPC/POPG脂质的相互作用比纯POPC脂质强得多，这与阴离子脂质双层上Aβ吸附和原纤维化增强的实验观察结果一致。虽然静电相互作用是驱动 p3 吸附在双层表面的主要吸引力，但 p3 五聚体在脂质双层上的吸附（优先 C 端 β 链面向双层表面）是 p3 肽-脂质双层和离子-p3-双层相互作用之间不同竞争的最终结果。更重要的是，发现 Ca2+ 离子形成离子桥，将 p3 的带负电荷的残基与脂质双层的阴离子头基结合起来，形成 Aβ–Ca2+–PO4− 复合物。与脂质双层和 Ca2+ 离子桥结合的密集 Ca2+ 可能会导致 Ca2+ 止血作用的交替，从而导致神经元功能障碍和死亡。这项工作在原子水平上深入了解 Aβ 肽和脂质双层的相互结构、动力学和相互作用，从而扩展了我们对淀粉样蛋白诱导的膜破坏的复杂行为的理解。
Interaction of p3 (Aβ17-42) peptides with cell membrane is crucial for the understanding of amyloid toxicity associated with Alzheimer’s disease (AD). Such p3-membrane interactions are considered to induce the disruption of membrane permeability and integrity, but the exact mechanisms of how p3 aggregates, particularly small p3 oligomers, induce receptor-independent membrane disruption are not yet completely understood. Here, we investigate the adsorption, orientation, and surface interaction of the p3 pentamer with lipid bilayers composed of both pure zwitterionic POPC (palmitoyl-oleyl-phosphatidylcholine) and mixed anionic POPC/POPG (palmitoyl-oleyl-phosphatidylglycerol) (3:1) lipids using explicit-solvent molecular dynamics (MD) simulations. MD simulation results show that the p3 pentamer has much stronger interactions with mixed POPC/POPG lipids than pure POPC lipids, consistent with experimental observation that Aβ adsorption and fibrililation are enhanced on anionic lipid bilayers. Although electrostatic interactions are main attractive forces to drive the p3 to adsorb on the bilayer surface, the adsorption of the p3 pentamer on the lipid bilayer with a preferential C-terminal β-strands facing toward the bilayer surface is a net outcome of different competitions between p3 peptides-lipid bilayer and ions-p3-bilayer interactions. More importantly, Ca2+ ions are found to form ionic bridges to associate negatively charged residues of p3 with anionic headgroups of the lipid bilayer, resulting in Aβ–Ca2+–PO4− complexes. Intensive Ca2+ bound to lipid bilayer and Ca2+ ionic bridges may lead to the alternation of Ca2+ hemostasis responsible for neuronal dysfunction and death. This work provides insights into the mutual structure, dynamics, and interactions of both Aβ peptides and lipid bilayer at the atomic level, which expand our understanding of the complex behavior of amyloid-induced membrane disruption.
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