Muhammedkutty Fidha Nazreen Kunnath, Zhou Huan-Xiang
Department of Chemistry, University of Illinois Chicago, Chicago, IL, USA.
Department of Physics, University of Illinois Chicago, Chicago, IL, USA.
bioRxiv. 2024 Sep 8:2024.09.05.611426. doi: 10.1101/2024.09.05.611426.
Alzheimer's disease (AD) is caused by the assembly of amyloid-beta (Aβ) peptides into oligomers and fibrils. Endogenous Aβ aggregation may be assisted by cell membranes, which can accelerate the nucleation step enormously, but knowledge of membrane-assisted aggregation is still very limited. Here we used extensive MD simulations to structurally and energetically characterize key intermediates along the membrane-assisted aggregation pathways of Aβ40. Reinforcing experimental observations, the simulations reveal unique roles of GM1 ganglioside and cholesterol in stabilizing membrane-embedded β-sheets and of Y10 and K28 in the ordered release of a small oligomeric seed into solution. The same seed leads to either an open-shaped or R-shaped fibril, with significant stabilization provided by inter- or intra-subunit interfaces between a straight β-sheet (residues Q15-D23) and a bent β-sheet (residues A30-V36). This work presents the first comprehensive picture of membrane-assisted aggregation of Aβ40, with broad implications for developing AD therapies and rationalizing disease-specific polymorphisms of amyloidogenic proteins.
阿尔茨海默病（AD）是由β-淀粉样蛋白（Aβ）肽组装成寡聚体和原纤维引起的。内源性Aβ聚集可能受到细胞膜的辅助，细胞膜可极大地加速成核步骤，但目前关于膜辅助聚集的了解仍然非常有限。在此，我们使用了广泛的分子动力学（MD）模拟，从结构和能量角度对Aβ40膜辅助聚集途径中的关键中间体进行了表征。模拟结果强化了实验观察，揭示了GM1神经节苷脂和胆固醇在稳定膜嵌入β-折叠中的独特作用，以及Y10和K28在小寡聚种子有序释放到溶液中的作用。同一种子可导致开放形或R形原纤维，由直β-折叠（残基Q15-D23）和弯曲β-折叠（残基A30-V36）之间的亚基间或亚基内界面提供显著稳定作用。这项工作首次全面呈现了Aβ40膜辅助聚集的情况，对开发AD治疗方法以及解释淀粉样蛋白生成蛋白的疾病特异性多态性具有广泛意义。
