Institut für Strukturbiologie und Biophysik, Strukturbiochemie, Forschungszentrum Jülich, 52425 Jülich, Germany.
J Am Chem Soc. 2010 Sep 29;132(38):13300-12. doi: 10.1021/ja103725c.
We model oligomers of the Alzheimer's amyloid β-peptide Aβ(1-42) in 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 Aβ(1-42) peptide 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.
我们在隐式膜中模拟阿尔茨海默病淀粉样 β-肽 Aβ（1-42）的低聚物，以深入了解淀粉样毒性的机制。有人提出 Aβ 低聚物是有毒物质，由于形成孔，导致神经元细胞中的膜破裂。我们使用 basin-hopping 全局优化来识别插入脂质双层的 Aβ（1-42）肽单体和小低聚物（最多至八聚体）的最稳定结构。为了提高 basin-hopping 方法的效果，我们引入了 basin-hopping 平行温度方案和低聚物生成过程。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的链-转折-链模式。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彼此相对旋转或移位的独特四聚体单元。这种效应导致有利的肽-肽相互作用增加，从而稳定插入膜的八聚体。基于这些结果，我们提出 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化实验的结果一致。
