Convertino Marino, Pellarin Riccardo, Catto Marco, Carotti Angelo, Caflisch Amedeo
Department of Biochemistry, University of Zurich, CH-8057 Zurich, Switzerland.
Protein Sci. 2009 Apr;18(4):792-800. doi: 10.1002/pro.87.
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 (Abeta) 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 Abeta 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 Abeta heptapeptide segment H(14)QKLVFF(20), the hydrophobic stretch that promotes the Abeta 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 Abeta(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 Abeta oligomers, providing useful insights for the design of small-molecule inhibitors of aggregation with therapeutic potential in Alzheimer's disease.
淀粉样蛋白聚集与多种神经退行性综合征有关，其中最常见的是阿尔茨海默病。在这种病理状态下，β-淀粉样肽（Aβ）聚集成寡聚体、原纤维和纤维，最终形成斑块，这是阿尔茨海默病的特征性标志。最近发现了几种能够抑制Aβ聚集过程的低分子量化合物；然而，迄今为止，关于它们与寡聚体和纤维相互作用的详细描述尚付阙如。在此，利用分子动力学模拟研究了两种相对相似的三环平面化合物，即9,10-蒽醌（AQ）和蒽（AC），对Aβ七肽片段H(14)QKLVFF(20)聚集早期阶段的影响，该片段是促进Aβ自组装的疏水区域。模拟结果表明，AQ比AC更能干扰β-折叠的形成。特别是，AQ插入到β-折叠中，因为化合物与肽主链之间的极性相互作用破坏了链间氢键，从而有利于无序状态。硫黄素T结合试验表明，AQ能显著降低聚集的Aβ(1-40)肽的量，而AC则不能。综上所述，计算机模拟和体外实验结果表明，AQ引起的结构扰动可显著影响有序寡聚化。此外，模拟在原子水平上揭示了AQ与Aβ寡聚体之间的相互作用，为设计具有治疗阿尔茨海默病潜力的小分子聚集抑制剂提供了有用的见解。
