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

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 C₆₀ 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 C₆₀ and water-soluble fullerenol C₆₀(OH)₆/C₆₀(OH)₁₂ (C₆₀ carrying 6/12 hydroxyl groups) with preformed Aβ_40/42 protofibrils by multiple molecular dynamics simulations. We found that when binding to the Aβ₄₂ protofibril, C₆₀, C₆₀(OH)₆ and C₆₀(OH)₁₂ exhibit distinct binding dynamics, binding sites and peptide interaction. The increased number of hydroxyl groups C₆₀ carries leads to slower binding dynamics and weaker binding strength. Binding free energy analysis demonstrates that the C₆₀/C₆₀(OH)₆ molecule primarily binds to the C-terminal residues 31-41, whereas C₆₀(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 C₆₀ carries more hydroxyls. In addition, the C₆₀(OH)₆ molecule has high affinity to form hydrogen bonds with protein backbones. The binding behaviors of C₆₀/C₆₀(OH)₆/C₆₀(OH)₁₂ to the Aβ₄₀ protofibril resemble with those to Aβ₄₂. Our work provides a detailed picture of fullerene/fullerenols binding to Aβ protofibril, and is helpful to understand the underlying inhibitory mechanism.