Distinct Binding Dynamics, Sites and Interactions of Fullerene and Fullerenols with Amyloid-β Peptides Revealed by Molecular Dynamics Simulations.

The pathology Alzheimer's disease (AD) is associated with the self-assembly of amyloid-β (Aβ) peptides into β-sheet enriched fibrillar aggregates. A promising treatment strategy is focused on the inhibition of amyloid fibrillization of Aβ peptide. Fullerene C is proved to effectively inhibit Aβ fibrillation while the poor water-solubility restricts its use as a biomedicine agent. In this work, we examined the interaction of fullerene C and water-soluble fullerenol C(OH)/C(OH) (C carrying 6/12 hydroxyl groups) with preformed Aβ protofibrils by multiple molecular dynamics simulations. We found that when binding to the Aβ protofibril, C, C(OH) and C(OH) exhibit distinct binding dynamics, binding sites and peptide interaction. The increased number of hydroxyl groups C carries leads to slower binding dynamics and weaker binding strength. Binding free energy analysis demonstrates that the C/C(OH) molecule primarily binds to the C-terminal residues 31-41, whereas C(OH) favors to bind to N-terminal residues 4-14. The hydrophobic interaction plays a critical role in the interplay between Aβ and all the three nanoparticles, and the π-stacking interaction gets weakened as C carries more hydroxyls. In addition, the C(OH) molecule has high affinity to form hydrogen bonds with protein backbones. The binding behaviors of C/C(OH)/C(OH) to the Aβ protofibril resemble with those to Aβ. Our work provides a detailed picture of fullerene/fullerenols binding to Aβ protofibril, and is helpful to understand the underlying inhibitory mechanism.