State Key Laboratory of Surface Physics, Key Laboratory for Computational Physical Sciences (Ministry of Education) and Department of Physics, Fudan University, 220 Handan Road, Shanghai, 200433, China.
Nanoscale. 2014 Aug 21;6(16):9752-62. doi: 10.1039/c4nr01005a.
Amyloid deposits are implicated in the pathogenesis of many neurodegenerative diseases such as Alzheimer's disease (AD). The inhibition of β-sheet formation has been considered as the primary therapeutic strategy for AD. Increasing data show that nanoparticles can retard or promote the fibrillation of amyloid-β (Aβ) peptides depending on the physicochemical properties of nanoparticles, however, the underlying molecular mechanism remains elusive. In this study, our replica exchange molecular dynamics (REMD) simulations show that fullerene nanoparticle - C60 (with a fullerene : peptide molar ratio greater than 1 : 8) can dramatically prevent β-sheet formation of Aβ(16-22) peptides. Atomic force microscopy (AFM) experiments further confirm the inhibitory effect of C60 on Aβ(16-22) fibrillation, in support of our REMD simulations. An important finding from our REMD simulations is that fullerene C180, albeit with the same number of carbon atoms as three C60 molecules (3C60) and smaller surface area than 3C60, displays an unexpected stronger inhibitory effect on the β-sheet formation of Aβ(16-22) peptides. A detailed analysis of the fullerene-peptide interaction reveals that the stronger inhibition of β-sheet formation by C180 results from the strong hydrophobic and aromatic-stacking interactions of the fullerene hexagonal rings with the Phe rings relative to the pentagonal rings. The strong interactions between the fullerene nanoparticles and Aβ(16-22) peptides significantly weaken the peptide-peptide interaction that is important for β-sheet formation, thus retarding Aβ(16-22) fibrillation. Overall, our studies reveal the significant role of fullerene hexagonal rings in the inhibition of Aβ(16-22) fibrillation and provide novel insight into the development of drug candidates against Alzheimer's disease.
淀粉样蛋白沉积与许多神经退行性疾病的发病机制有关，如阿尔茨海默病（AD）。β-折叠形成的抑制被认为是 AD 的主要治疗策略。越来越多的数据表明，纳米颗粒可以根据纳米颗粒的物理化学性质来延缓或促进淀粉样β（Aβ）肽的纤颤，然而，其潜在的分子机制仍不清楚。在这项研究中，我们的复制交换分子动力学（REMD）模拟表明，富勒烯纳米颗粒-C60（富勒烯与肽的摩尔比大于 1:8）可以显著阻止 Aβ（16-22）肽的β-折叠形成。原子力显微镜（AFM）实验进一步证实了 C60 对 Aβ（16-22）纤颤的抑制作用，支持了我们的 REMD 模拟。我们的 REMD 模拟的一个重要发现是，尽管富勒烯 C180 具有与三个 C60 分子（3C60）相同数量的碳原子和比 3C60 更小的表面积，但对 Aβ（16-22）肽的β-折叠形成显示出出人意料的更强抑制作用。对富勒烯-肽相互作用的详细分析表明，C180 对β-折叠形成的更强抑制作用是由于富勒烯六边形环与苯环之间的强疏水性和芳香堆积相互作用相对于五边形环。富勒烯纳米颗粒与 Aβ（16-22）肽之间的强烈相互作用显著削弱了对β-折叠形成重要的肽-肽相互作用，从而延缓了 Aβ（16-22）的纤颤。总的来说，我们的研究揭示了富勒烯六边形环在抑制 Aβ（16-22）纤颤中的重要作用，并为开发针对阿尔茨海默病的药物候选物提供了新的见解。
