Transmembrane structures for Alzheimer's Aß(1-42) oligomers.
Transmembrane structures for Alzheimer's Aß(1-42) oligomers.
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阿尔茨海默病 Aα(1-42) 寡聚物的跨膜结构。
DOI：
10.1021/ja103725c
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发表时间：
2010
影响因子：
15
通讯作者：
Strodel B
中科院分区：
文献类型：
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作者：
Strodel B
我们在隐式膜中模拟阿尔茨海默氏淀粉样蛋白β-肽Aβ1− 42的寡聚体，以深入了解淀粉样蛋白毒性的机制。已经表明Aβ寡聚体是毒性物质，由于孔形成而导致神经元细胞中的膜破坏。我们使用basin-hopping全局优化来确定Aβ1− 42肽单体和小寡聚体（直到插入脂质双层的八聚体）的最稳定结构。为了提高跳盆方法的功效，我们引入了跳盆平行回火方案和低聚物生成程序。单体的最稳定的跨膜结构被鉴定为β-折叠，其表现出在NMR实验中观察到的典型链-转角-链基序。我们发现二聚体到六聚体的有序β-折叠，而对于八聚体，我们观察到有序结构分离成不同的四聚体单元，这些单元相对于彼此旋转或移位。这种效应导致有利的肽-肽相互作用增加，从而稳定膜插入的八聚体。基于这些结果，我们认为Aβ孔可能由四聚体和六聚体β折叠亚基组成。这些Aβ孔模型与生物物理和生物化学实验结果一致。
We model oligomers of the Alzheimer’s amyloid β-peptide Aβ1−42in an implicit membrane to obtain insight into the mechanism of amyloid toxicity. It has been suggested that Aβ oligomers are the toxic species, causing membrane disruption in neuronal cells due to pore formation. We use basin-hopping global optimization to identify the most stable structures for the Aβ1−42peptide monomer and small oligomers up to the octamer inserted into a lipid bilayer. To improve the efficacy of the basin-hopping approach, we introduce a basin-hopping parallel tempering scheme and an oligomer generation procedure. The most stable membrane-spanning structure for the monomer is identified as a β-sheet, which exhibits the typical strand-turn-strand motif observed in NMR experiments. We find ordered β-sheets for the dimer to the hexamer, whereas for the octamer, we observe that the ordered structures separate into distinct tetrameric units that are rotated or shifted with respect to each other. This effect leads to an increase in favorable peptide−peptide interactions, thereby stabilizing the membrane-inserted octamer. On the basis of these results, we suggest that Aβ pores may consist of tetrameric and hexameric β-sheet subunits. These Aβ pore models are consistent with the results of biophysical and biochemical experiments.