Binding Mechanisms of Amyloid-like Peptides to Lipid Bilayers and Effects of Divalent Cations
Binding Mechanisms of Amyloid-like Peptides to Lipid Bilayers and Effects of Divalent Cations
复制标题
类淀粉样肽与脂质双层的结合机制及二价阳离子的影响
DOI：
10.1021/acschemneuro.1c00140
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发表时间：
2021
影响因子：
5
通讯作者：
Dias, Cristiano L.
中科院分区：
文献类型：
--
作者：
Yang, Yanxing;Jalali, Sharareh;Nilsson, Bradley L.;Dias, Cristiano L.
在几种神经退行性疾病中，细胞毒性可以从淀粉样蛋白聚集体对脂质膜产生的损伤中出现。解释这种损伤的细节知之甚少，包括单个淀粉样肽在聚集前如何与磷脂膜相互作用。在这里，我们使用全原子分子动力学模拟来研究淀粉样蛋白膜相互作用的分子机制和钙离子在这种相互作用中发挥的作用。本研究中使用了已知自组装成淀粉样蛋白原纤维和由两性离子和阴离子脂质制成的双层的模型肽。我们发现，静电和疏水相互作用有助于肽双层结合。特别是，肽对脂质双层的吸引力主要由脂质头部基团的正残基和负磷酸基团之间的静电相互作用决定。这种吸引力是强的阴离子双层比两性离子的。在我们的模拟中，疏水性驱动非极性残基埋入双层内部，产生强结合。此外，我们观察到，在钙离子的存在下，肽的双层的吸引力显着降低。这是由于钙离子与脂质头部基团的负磷酸盐部分结合，这使得磷脂双层具有净正电荷。肽与膜的强结合在钙离子存在下不太频繁地发生，并且涉及“Ca2+桥”的形成。
In several neurodegenerative diseases, cell toxicity can emerge from damage produced by amyloid aggregates to lipid membranes. The details accounting for this damage are poorly understood including how individual amyloid peptides interact with phospholipid membranes before aggregation. Here, we use all-atom molecular dynamics simulations to investigate the molecular mechanisms accounting for amyloid–membrane interactions and the role played by calcium ions in this interaction. Model peptides known to self-assemble into amyloid fibrils and bilayer made from zwitterionic and anionic lipids are used in this study. We find that both electrostatic and hydrophobic interactions contribute to peptide–bilayer binding. In particular, the attraction of peptides to lipid bilayers is dominated by electrostatic interactions between positive residues and negative phosphate moieties of lipid head groups. This attraction is stronger for anionic bilayers than for zwitterionic ones. Hydrophobicity drives the burial of nonpolar residues into the interior of the bilayer producing strong binding in our simulations. Moreover, we observe that the attraction of peptides to the bilayer is significantly reduced in the presence of calcium ions. This is due to the binding of calcium ions to negative phosphate moieties of lipid head groups, which leaves phospholipid bilayers with a net positive charge. Strong binding of the peptide to the membrane occurs less frequently in the presence of calcium ions and involves the formation of a “Ca2+bridge”.