Effects of applied surface-tension on membrane-assisted Aβ aggregation
Effects of applied surface-tension on membrane-assisted Aβ aggregation
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应用表面张力对膜辅助 Aβ 聚集的影响
DOI：
10.1039/d1cp02642a
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发表时间：
2021
影响因子：
3.3
通讯作者：
Matysiak, Silvina
中科院分区：
文献类型：
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作者：
Sahoo, Abhilash;Matysiak, Silvina
蛋白基（Aβ）聚集体在具有不同结构特性的细胞膜上的积累被普遍认为是阿尔茨海默病发病的关键步骤。但实验和计算方面的挑战使得这种生物物理表征变得困难。特别是，连接生物膜组织和Aβ聚集的研究是有限的。虽然实验表明，在阿尔茨海默病的背景下，增加的膜曲率导致更快的a β肽聚集，但这种关系的机制解释尚不清楚。在这项工作中，我们利用基于物理的粗粒度模型进行分子模拟，以解决和理解弯曲细胞膜与模型模板肽a β 16-22聚集之间的关系。与实验结果一致，我们的模拟也表明增加的肽聚集和膜曲率之间呈正相关。更多弯曲的膜具有更高的脂质堆积缺陷，这些缺陷参与肽疏水性基团并促进更快的扩散，导致肽纤维结构。此外，我们还策划了肽聚集对膜结构和组织的影响。界面肽聚集导致异质性头群-肽相互作用和脂质头群区域诱导的拥挤效应，导致更有序的头群区域和膜核处无序的脂质尾部。这项工作提出了生物膜局部结构和组织与a β肽聚集之间关系的机制和形态学概述。
Accumulation of protein-based (Aβ) aggregates on cellular membranes with varying structural properties is commonly recognized as the key step in Alzheimer's pathogenesis. But experimental and computational challenges have made this biophysical characterization difficult. In particular, studies connecting biological membrane organization and Aβ aggregation are limited. While experiments have suggested that an increased membrane curvature results in faster Aβ peptide aggregation in the context of Alzheimer's disease, a mechanistic explanation for this relation is missing. In this work, we are leveraging molecular simulations with a physics-based coarse grained model to address and understand the relationships between curved cellular membranes and aggregation of a model template peptide Aβ 16–22. In agreement with experimental results, our simulations also suggest a positive correlation between increased peptide aggregation and membrane curvature. More curved membranes have higher lipid packing defects that engage peptide hydrophobic groups and promote faster diffusion leading to peptide fibrillar structures. In addition, we curated the effects of peptide aggregation on the membrane's structure and organization. Interfacial peptide aggregation results in heterogeneous headgroup–peptide interactions and an induced crowding effect at the lipid headgroup region, leading to a more ordered headgroup region and disordered lipid-tails at the membrane core. This work presents a mechanistic and morphological overview of the relationships between the biomembrane local structure and organization, and Aβ peptide aggregation.