9,10-Anthraquinone hinders β-aggregation: How does a small molecule interfere with Aβ-peptide amyloid fibrillation?
9,10-Anthraquinone hinders β-aggregation: How does a small molecule interfere with Aβ-peptide amyloid fibrillation?
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DOI：
10.1002/pro.87
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发表时间：
2009-04-01
期刊：
影响因子：
8
通讯作者：
Caflisch, Amedeo
中科院分区：
文献类型：
--
作者：
Convertino, Marino;Pellarin, Riccardo;Caflisch, Amedeo
淀粉样蛋白聚集与许多神经退行性综合征有关，最常见的是阿尔茨海默病。在这种病理学中，β-淀粉样肽（A β）聚集成寡聚体、原纤维和原纤维，并最终聚集成斑块，这构成了阿尔茨海默病的特征性标志。最近已经发现了几种能够损害A β聚集过程的低分子量化合物;然而，迄今为止缺少对其与低聚物和原纤维相互作用的详细描述。在这里，分子动力学模拟用于研究两种相对相似的三环平面化合物，即9，10-蒽醌（AQ）和蒽（AC）对A β七肽片段H（14）QKLVFF（20）聚集早期阶段的影响，该疏水伸展促进A β自组装。模拟显示，AQ比AC更干扰β-折叠的形成。特别地，AQ嵌入β-折叠中，因为化合物和肽骨架之间的极性相互作用使链间氢键不稳定，从而有利于无序。硫磺素T结合试验表明，AQ而不是AC可明显减少聚集的A β（1-40）肽的量。两者合计，在计算机和体外结果提供的证据表明，AQ的结构扰动可以显着影响有序的寡聚化。此外，模拟揭示了原子水平上的AQ和A β寡聚体之间的相互作用，为设计具有治疗潜力的阿尔茨海默病聚集的小分子抑制剂提供了有用的见解。
Amyloid aggregation is linked to a number of neurodegenerative syndromes, the most prevalent one being Alzheimer's disease. In this pathology, the beta-amyloid peptides (A beta) aggregate into oligomers, protofibrils, and fibrils and eventually into plaques, which constitute the characteristic hallmark of Alzheimer's disease. Several low-molecular-weight compounds able to impair the A beta aggregation process have been recently discovered; yet, a detailed description of their interactions with oligomers and fibrils is hitherto missing. Here, molecular dynamics simulations are used to investigate the influence of two relatively similar tricyclic, planar compounds, that is, 9, 10-anthraquinone (AQ) and anthracene (AC), on the early phase of the aggregation of the A beta heptapeptide segment H(14)QKLVFF(20), the hydrophobic stretch that promotes the A beta self-assembly. The simulations show that AQ interferes with beta-sheet formation more than AC. In particular, AQ intercalates into the beta-sheet because polar interactions between the compound and the peptide backbone destabilize the interstrand hydrogen bonds, thereby favoring disorder. The thioflavin T-binding assay indicates that AQ, but not AC, sensibly reduces the amount of aggregated A beta(1-40) peptide. Taken together, the in silico and in vitro results provide evidence that structural perturbations by AQ can remarkably affect ordered oligomerization. Moreover, the simulations shed light at the atomic level on the interactions between AQ and A beta oligomers, providing useful insights for the design of small-molecule inhibitors of aggregation with therapeutic potential in Alzheimer's disease.