Pathways of amyloid-beta absorption and aggregation in a membranous environment
Pathways of amyloid-beta absorption and aggregation in a membranous environment
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膜环境中β-淀粉样蛋白吸收和聚集的途径
DOI：
10.1039/c9cp00040b
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发表时间：
2019
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;Xu, Hongcheng;Matysiak, Silvina
错误折叠的寡聚淀粉样β（Aβ）肽在脂膜上的聚集已被确定为阿尔茨海默病发病机制中的主要事件。然而，这种膜辅助Aβ聚集的结构和动力学特征尚未得到很好的表征。肽聚集途径中动态分子水平相互作用的微观表征在计算和实验上都具有挑战性。在这项工作中，我们从分子相互作用的微观角度探索膜诱导Aβ 16-22（K-L-V-F-F-A-E）聚集的差异模式。采用基于物理的粗粒分子动力学（CG-MD）模拟研究了脂质头基电荷-两性离子（1-棕榈酰-2-油酰-sn-甘油-3-磷酸胆碱：POPC）和阴离子（1-棕榈酰-2-油酰-sn-甘油-3-磷酸-L-丝氨酸：POPS）-对Aβ 16-22肽聚集的影响。我们的分析提出了一个广泛的概述多种途径肽的吸收和生物力学力量肽折叠和聚集。与实验观察结果一致，阴离子POPS分子促进Aβ肽中的扩展构型，与POPC相比，这有助于更快地出现有序的富含β-片层的肽组装体，表明更快的原纤化。此外，由于较高的肽-脂质相互作用和较慢的脂质扩散，POPS中肽聚集的累积速率较低，导致多个不同的有序肽聚集体，可作为后续Aβ聚集的成核种子。这项研究提供了一个实验观察到的聚集模式的计算机模拟评估，提出了新的形态学见解，并强调了脂质头基化学在调节肽的吸收和聚集过程的重要性。
Aggregation of misfolded oligomeric amyloid-beta (Aβ) peptides on lipid membranes has been identified as a primary event in Alzheimer's pathogenesis. However, the structural and dynamical features of this membrane assisted Aβ aggregation have not been well characterized. The microscopic characterization of dynamic molecular-level interactions in peptide aggregation pathways has been challenging both computationally and experimentally. In this work, we explore differential patterns of membrane-induced Aβ 16–22 (K–L–V–F–F–A–E) aggregation from the microscopic perspective of molecular interactions. Physics-based coarse-grained molecular dynamics (CG-MD) simulations were employed to investigate the effect of lipid headgroup charge – zwitterionic (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine: POPC) and anionic (1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine: POPS) – on Aβ 16–22 peptide aggregation. Our analyses present an extensive overview of multiple pathways for peptide absorption and biomechanical forces governing peptide folding and aggregation. In agreement with experimental observations, anionic POPS molecules promote extended configurations in Aβ peptides that contribute towards faster emergence of ordered β-sheet-rich peptide assemblies compared to POPC, suggesting faster fibrillation. In addition, lower cumulative rates of peptide aggregation in POPS due to higher peptide–lipid interactions and slower lipid diffusion result in multiple distinct ordered peptide aggregates that can serve as nucleation seeds for subsequent Aβ aggregation. This study provides an in-silico assessment of experimentally observed aggregation patterns, presents new morphological insights and highlights the importance of lipid headgroup chemistry in modulating the peptide absorption and aggregation process.