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.

The pathogenesis of Alzheimer's disease (AD) is associated with the aggregation of amyloid-β (Aβ) peptides into toxic aggregates with ?-sheet character. In a previous computational study, we showed that pristine single-walled carbon nanotubes (SWCNTs) can inhibit the formation of β-sheet-rich oligomers in the central hydrophobic core fragment of Aβ (Aβ16-22). However, the poor solubility of SWCNTs in water hinders their use in biomedical applications and nanomedicine. Here, we investigate the influence of hydroxylated SWCNT, a water-soluble SWCNT derivative, on the aggregation of Aβ16-22 peptides using all-atom explicit-water replica exchange molecular dynamics simulations. Our results show that hydroxylated SWCNTs can significantly inhibit β-sheet formation and shift the conformations of Aβ16-22 oligomers from ordered β-sheet-rich structures toward disordered coil aggregates. Detailed analyses of the SWCNT-Aβ interaction reveal that the inhibition of β-sheet formation by hydroxylated SWCNTs mainly results from strong electrostatic interactions between the hydroxyl groups of SWCNTs and the positively charged residue K16 of Aβ16-22 and hydrophobic and aromatic stacking interactions between SWCNTs and F19 and F20. In addition, our atomic force microscopy and thioflavin T fluorescence experiments confirm the inhibitory effect of both pristine and hydroxylated SWCNTs on Aβ16-22 fibrillization, in support of our previous and present replica exchange molecular dynamics simulation results. These results demonstrate that hydroxylated SWCNTs efficiently inhibit the aggregation of Aβ16-22; in addition, they offer molecular insight into the inhibition mechanism, thus providing new clues for the design of therapeutic drugs against amyloidosis.

A recent experimental study reported that termini-uncapped Aβ(16-22) (with sequence KLVFFAE) peptides self-assembled into nanofibrils at pH 2.0. The oligomerization of this uncapped peptide at atomic level in acidic pH condition remains to be determined, as computational studies mainly focus on the self-assembly of capped Aβ(16-22) peptides at neutral pH condition. In this study, using replica exchange molecular dynamics (REMD) simulations with explicit solvent, we investigated the octameric structures of the uncapped Aβ(16-22) and its F19W variant at acidic pH condition. Our simulations reveal that the Aβ(16-22) octamers adopt various conformations, including closed β-barrels, bilayer β-sheets, and disordered aggregates. The closed β-barrel conformation is particularly interesting, as the cylindrical β-barrel has been reported recently as a cytotoxic species. Interpeptide contact probability analyses between all pairs of residues reveal that the hydrophobic and aromatic stacking interactions between F19 residues play an essential role in the formation of β-barrels and bilayer β-sheets. The importance of F19 and the steric effect on the structures of Aβ(16-22) octamers are further examined by REMD simulation of F19W mutant. This REMD run shows that substitution of F19 by W with a more bulky aromatic side chain significantly reduces the β-sheet content and in turn enhances the population of disordered aggregates, indicating that the steric effect significantly affect the self-assembly of low molecular weight Aβ(16-22) oligomers.

C60(OH)24inhibits hIAPP aggregation by suppressing the fibril-prone structure and destabilizes hIAPP protofibrils by binding to the amyloid core region.