The molecular mechanism of fullerene-inhibited aggregation of Alzheimer's β-amyloid peptide fragment

Abstract

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.