De Novo Transmembrane Aggregation of Aβ10–40 Peptides in an Anionic Lipid Bilayer,Journal of Chemical Information and Modeling

当前位置： X-MOL 学术 › J. Chem. Inf. Model. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

De Novo Transmembrane Aggregation of Aβ10–40 Peptides in an Anionic Lipid Bilayer
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2022-12-01 , DOI: 10.1021/acs.jcim.2c01192
James Vergilio ₁ , Christopher Lockhart ₁ , Dmitri K Klimov ₁

Affiliation

Using the all-atom model and 10 μs serial replica-exchange molecular dynamics (SREMD), we investigated the binding of Alzheimer’s Aβ10–40 peptides to the anionic dimyristoylphosphatidylcholine/dimyristoylphosphatidylglycerol (DMPC/DMPG) lipid bilayer. Our objective was to probe de novo transmembrane Aβ10–40 aggregation and to test the utility of SREMD. Our results are threefold. First, upon binding, Aβ10–40 adopts a helical structure in the C-terminus and deeply inserts into the bilayer. Binding is primarily controlled by electrostatic interactions of the peptides with water, ions, and lipids, particularly, anionic DMPG. Second, Aβ-bilayer interactions reorganize lipids in the proximity of the bound peptides, causing an influx of DMPG lipids into the Aβ binding footprint. Third and most important, computed free energy landscapes reveal that Aβ10–40 peptides partition into monomeric and dimeric species. The dimers result from transmembrane aggregation of the peptides and induce a striking lipid density void throughout both leaflets in the bilayer. There are multiple factors stabilizing transmembrane dimers, including van der Waals and steric interactions, electrostatic interactions, and hydrogen bonding, hydration, and entropic gains originating from dimer conformations and lipid disorder. We argue that helix dipole–dipole interactions underestimated in the all-atom force field must be a contributing factor to stabilizing antiparallel transmembrane dimers. We propose that transmembrane aggregates serve as mechanistic links between the populations of extra- and intracellular Aβ peptides. From the computational perspective, SREMD is found to be a viable alternative to traditional replica-exchange simulations.

中文翻译：

Aβ10-40 肽在阴离子脂质双层中的从头跨膜聚集

使用全原子模型和 10 μs 串行复制交换分子动力学 (SREMD)，我们研究了阿尔茨海默氏症 Aβ10–40 肽与阴离子二肉豆蔻酰磷脂酰胆碱/二肉豆蔻酰磷脂酰甘油 (DMPC/DMPG) 脂质双层的结合。我们的目标是从头探查跨膜 Aβ10-40 聚集和测试 SREMD 的效用。我们的结果是三方面的。首先，结合后，Aβ10-40 在 C 端采用螺旋结构并深深插入双层。结合主要由肽与水、离子和脂质（尤其是阴离子 DMPG）的静电相互作用控制。其次，Aβ-双层相互作用重组结合肽附近的脂质，导致 DMPG 脂质流入 Aβ 结合足迹。第三也是最重要的，计算出的自由能景观表明 Aβ10-40 肽分为单体和二聚体。二聚体由肽的跨膜聚集产生，并在双层的两个小叶中诱导显着的脂质密度空隙。有多种因素稳定跨膜二聚体，包括范德瓦尔斯和空间相互作用、静电相互作用以及氢键、水合和源自二聚体构象和脂质紊乱的熵增加。我们认为在全原子力场中被低估的螺旋偶极-偶极相互作用一定是稳定反平行跨膜二聚体的一个促成因素。我们建议跨膜聚集体充当细胞外和细胞内 Aβ 肽群之间的机械联系。从计算的角度来看，SREMD 被发现是传统副本交换模拟的可行替代方案。我们认为在全原子力场中被低估的螺旋偶极-偶极相互作用一定是稳定反平行跨膜二聚体的一个促成因素。我们建议跨膜聚集体充当细胞外和细胞内 Aβ 肽群之间的机械联系。从计算的角度来看，SREMD 被发现是传统副本交换模拟的可行替代方案。我们认为在全原子力场中被低估的螺旋偶极-偶极相互作用一定是稳定反平行跨膜二聚体的一个促成因素。我们建议跨膜聚集体充当细胞外和细胞内 Aβ 肽群之间的机械联系。从计算的角度来看，SREMD 被发现是传统副本交换模拟的可行替代方案。

更新日期：2022-12-01

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11