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.

Modeling and simulation of protein–surface interactions: achievements and challenges

“…Although easy to implement and perform, this method was shown to have a relatively large error range (Singh & Warshel, 2010) into the adsorption strength of a binding mode from a trajectory, a better sampling of configuration phase space is required for MD simulations. To reduce the effect of the insufficient sampling on the energy calculations, Xie et al (2014) used the REMD method for sampling the adsorption of the Aβ peptide to fullerenes. After clustering of the conformers, the MM-GBSA method was employed to obtain binding free energies for the largest clusters.…”

“…Binding free energy calculations of amyloidogenic apoC-II(60-70) peptide on fullerene, CNT and graphene using MD simulations showed that the binding affinity was weakest for the fullerene and strongest for the graphene due to reduced efficiency of π-stacking interactions between the aromatic side chains of the peptide and the fullerene and CNT arising from the increased surface curvature (Todorova et al 2013). Xie et al (2014) calculated the adsorption free energies of Alzheimer's β-amyloid peptide fragments (Aβ) to two different fullerene nanoparticle systems, C 180 and three C 60 (3C 60 ). They found tighter binding of the peptides on the larger C 180 .…”

Nanotechnology Based Theranostic Approaches in Alzheimer's Disease Management: Current Status and Future Perspective

“…Moreover, the D23–K28 salt bridge in this site can be destabilized by DMF, which is thought to be significant in the Aβ fibrillation. Additionally, Xie et al studied the molecular mechanism of inhibition of Alzheimer's Aβ peptide aggregation by fullerene [48]. Their results showed that significantly higher inhibition of β-sheet formation through fullerene is due to extreme lipophilic and aromatic π -stacking interactions of the C 60 hexagonal rings.…”

Modulating protein amyloid aggregation with nanomaterials

“…It was reported that strong interactions between the fullerene NPs and Aβ 16–22 fragments significantly weakened peptide-peptide contact, thus limiting amyloid fibrillization. 123 An additional study conducted by Sun et al investigated the effect of DMF on the conformation of Aβ 1–42 dimer. Computational simulations indicated that the interaction of DMFs with Aβ peptides also greatly impeded the formation of β-hairpins and inter-peptide β-sheets.…”