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.