Nagoya University, Department of Physics, Graduate school of Science, Nagoya, Aichi, 464-8602, Japan.
National Institutes of Natural Sciences, Research Center for Computational Science, Institute for Molecular Science, Okazaki, Aichi, 444-8585, Japan.
Sci Rep. 2019 May 2;9(1):6853. doi: 10.1038/s41598-019-43117-6.
Aggregates of amyloid-β (Aβ) peptide are well known to be the causative substance of Alzheimer's disease (AD). Recent studies showed that monosialotetrahexosylganglioside (GM1) clusters induce the pathological aggregation of Aβ peptide responsible for the onset and development of AD. However, the effect of GM1-glycan cluster on Aβ conformations has yet to be clarified. Interactions between Aβ peptide and GM1-glycan cluster is important for the earliest stage of the toxic aggregation on GM1 cluster. Here, we performed all-atom molecular dynamics (MD) simulations of Aβ40 on a recently developed artificial GM1-glycan cluster. The artificial GM1-glycan cluster facilitates the characterization of interactions between Aβ40 and multiple GM1-glycans. We succeeded in observing the binding of Aβ40 to the GM1-glycan cluster in all of our MD simulations. Results obtained from these MD simulations indicate the importance of HHQ (13-15) segment of Aβ40 for the GM1-glycan cluster recognition. This result is consistent with previous experimental studies regarding the glycan recognition of Aβ peptide. The recognition mechanism of HHQ (13-15) segment is mainly explained by non-specific stacking interactions between side-chains of histidine and rings of sugar residues, in which the HHQ regime forms coil and bend structures. Moreover, we found that Aβ40 exhibits helix structures at C-terminal side on the GM1-glycan cluster. The helix formation is the initial stage of the pathological aggregation at ceramide moieties of GM1 cluster. The binding of Lys28 to Neu triggers the helix formation at C-terminus side because the formation of a salt bridge between Lys28 and Neu leads to change of intrachain interactions of Aβ40. Our findings suggest that the pathological helix formation of Aβ40 is initiated at GM1-glycan moieties rather than lipid ceramide moieties.
淀粉样β（Aβ）肽的聚集体是众所周知的阿尔茨海默病（AD）的致病物质。最近的研究表明，单唾液酸四己糖神经节苷脂（GM1）簇诱导负责 AD 发病和发展的 Aβ肽的病理性聚集。然而，GM1-聚糖簇对 Aβ构象的影响尚未阐明。Aβ肽与 GM1-聚糖簇之间的相互作用对于 GM1 簇上的毒性聚集的最早阶段很重要。在这里，我们对最近开发的人工 GM1-聚糖簇上的 Aβ40 进行了全原子分子动力学（MD）模拟。人工 GM1-聚糖簇有助于表征 Aβ40 与多个 GM1-聚糖之间的相互作用。我们成功地在所有 MD 模拟中观察到 Aβ40 与 GM1-聚糖簇的结合。这些 MD 模拟结果表明，Aβ40 中的 HHQ（13-15）片段对于 GM1-聚糖簇的识别很重要。这一结果与以前关于 Aβ肽聚糖识别的实验研究一致。HHQ（13-15）片段的识别机制主要解释为组氨酸侧链和糖残基环之间的非特异性堆积相互作用，其中 HHQ 区形成线圈和弯曲结构。此外，我们发现 Aβ40 在 GM1-聚糖簇上的 C 末端侧表现出螺旋结构。螺旋形成是 GM1 簇神经酰胺部分发生病理性聚集的初始阶段。Lys28 与 Neu 结合触发 C 末端侧的螺旋形成，因为 Lys28 和 Neu 之间形成盐桥导致 Aβ40 链内相互作用的变化。我们的研究结果表明，Aβ40 的病理性螺旋形成是在 GM1-聚糖部分而不是脂质神经酰胺部分开始的。
