Jiao Yong, Yang Pin
Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Institute of Molecular Science, Shanxi University, Taiyuan 030006, China.
J Phys Chem B. 2007 Jul 5;111(26):7646-55. doi: 10.1021/jp0673359. Epub 2007 Jun 12.
The aggregation of an amyloid beta peptide (Abeta) into fibrils is a key pathological event in Alzheimer's disease (AD). Under certain conditions, Cu2+ markedly inhibits Abeta from aggregation and is considered as a potential factor in the normal brain preventing Abeta from aggregation. The possible mechanism of the inhibitory effect of Cu2+ was investigated for the first time by molecular dynamics (MD) simulations. On the basis of the radial distribution function analysis of the MD data, a novel strategy, the Q function, was proposed to explore the binding sites of Cu2+ by evaluating the coordination priority of atoms in Abeta, and the [6-5-5] tri-ring 4N binding mode of the Cu2+-Abeta complexes was found. The mechanism of the conformational transition of Abeta from the beta conformation to distorted beta conformations, which destabilizes the aggregation of Abeta into fibrils, was also revealed. All the results provide helpful clues for an improved understanding of the role of Cu2+ in the pathogenesis of AD and contribute to the development of an anti-amyloid therapeutic strategy.
淀粉样β肽（Aβ）聚集成纤维是阿尔茨海默病（AD）中的关键病理事件。在某些条件下，Cu2+显著抑制Aβ聚集，被认为是正常大脑中防止Aβ聚集的潜在因素。首次通过分子动力学（MD）模拟研究了Cu2+抑制作用的可能机制。基于MD数据的径向分布函数分析，提出了一种新策略——Q函数，通过评估Aβ中原子的配位优先级来探索Cu2+的结合位点，并发现了Cu2+-Aβ复合物的[6-5-5]三环4N结合模式。还揭示了Aβ从β构象转变为扭曲β构象的构象转变机制，这种转变破坏了Aβ聚集成纤维的稳定性。所有结果为更好地理解Cu2+在AD发病机制中的作用提供了有益线索，并有助于开发抗淀粉样蛋白治疗策略。
