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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 60 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 60 and water-soluble fullerenol C 60 (OH) 6 /C 60 (OH) 12 (C 60 carrying 6/12 hydroxyl groups) with preformed Aβ 40/42 protofibrils by multiple molecular dynamics simulations. We found that when binding to the Aβ 42 protofibril, C 60 , C 60 (OH) 6 and C 60 (OH) 12 exhibit distinct binding dynamics, binding sites and peptide interaction. The increased number of hydroxyl groups C 60 carries leads to slower binding dynamics and weaker binding strength. Binding free energy analysis demonstrates that the C 60 /C 60 (OH) 6 molecule primarily binds to the C-terminal residues 31-41, whereas C 60 (OH) 12 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 60 carries more hydroxyls. In addition, the C 60 (OH) 6 molecule has high affinity to form hydrogen bonds with protein backbones. The binding behaviors of C 60 /C 60 (OH) 6 /C 60 (OH) 12 to the Aβ 40 protofibril resemble with those to Aβ 42 . Our work provides a detailed picture of fullerene/fullerenols binding to Aβ protofibril, and is helpful to understand the underlying inhibitory mechanism.

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