a Bioinformatics Infrastructure Facility, Center of Excellence in Bioinformatics, Department of Biochemistry , University of Lucknow , Lucknow 226007 , India.
J Biomol Struct Dyn. 2018 Feb;36(2):407-422. doi: 10.1080/07391102.2017.1279078. Epub 2017 Jan 24.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive accumulation of amyloid-beta (Aβ) peptides in brain. In the present study, two familial Aβ42 mutations, namely A2V (harmful) and A2T (protective) have been analyzed and compared with the wild-type (WT) by performing all-atom molecular dynamics (MD) simulations in the absence and presence of curcumin, a well-known inhibitor of Aβ plaque formation. Mutant A2V was found to exhibit highest stability followed by WT and mutant A2T in the absence of curcumin. This stability trend was found to be reversed in the presence of curcumin, suggesting a significant change in the conformational landscape of Aβ42 folding. Due to significant differences in the folding and interaction patterns of the mutants A2V and A2T, curcumin exhibited higher binding affinity for mutant A2T as compared to that of A2V. To the best of our knowledge, this is the first report on the effect of curcumin binding on structural landscapes of the two contrasting point mutants providing an understanding of the basis of Aβ plaque formation and its prevention by curcumin.
阿尔茨海默病（AD）是一种神经退行性疾病，其特征是大脑中淀粉样β（Aβ）肽的进行性积累。在本研究中，通过在没有和存在姜黄素的情况下进行全原子分子动力学（MD）模拟，分析并比较了两种家族性 Aβ42 突变体，即 A2V（有害）和 A2T（保护）与野生型（WT）。在没有姜黄素的情况下，突变体 A2V 表现出最高的稳定性，其次是 WT 和突变体 A2T。在存在姜黄素的情况下，这种稳定性趋势被逆转，表明 Aβ42 折叠的构象景观发生了显著变化。由于突变体 A2V 和 A2T 的折叠和相互作用模式存在显著差异，姜黄素对突变体 A2T 的结合亲和力高于 A2V。据我们所知，这是首次报道姜黄素结合对两种对比点突变体结构景观的影响，为了解 Aβ斑块形成的基础及其被姜黄素预防提供了依据。
