Inhibitory effect of hydrophobic fullerenes on the β-sheet-rich oligomers of a hydrophilic GNNQQNY peptide revealed by atomistic simulations

Abstract

Increasing numbers of experiments show that carbon nanoparticles can significantly influence protein fibrillation, a process associated with many human amyloidosis. Our previous studies demonstrate that fullerenes and carbon nanotubes can markedly inhibit the formation of β-sheet-rich oligomers and amyloid fibrils of the hydrophobic KLVFFAE peptide, the central hydrophobic core fragment of Alzheimer's amyloid-β protein, mostly through hydrophobic and aromatic-stacking interactions. In this study, the effect of hydrophobic fullerene C₆₀ on the oligomeric structures of the hydrophilic GNNQQNY peptide, the key amyloid-forming fragment of yeast prion protein Sup35, is investigated by extensive replica exchange molecular dynamics simulations. Our simulations, starting from eight random chains, show that fullerene can greatly impede the β-sheet formation of the GNNQQNY peptide and induce oligomer shifting from various β-sheet-rich structures to disordered coil conformations. Strikingly, fullerenes completely prevent fibril-like bilayer β-sheets, formed by GNNQQNY peptides alone. We find that C₆₀ molecules interact strongly with the nonpolar aliphatic groups of polar residues N3, Q4 and Q5 and increase the water exposure of the peptide backbone, thus block the inter-peptide N3–Q4, Q4–Q4 and Q4–Q5 interactions which are crucial for oligomerization and β-sheet formation. These results, together with our previous studies on the KLVFFAE peptide, suggest that hydrophobic fullerenes could inhibit the aggregation of both hydrophobic and hydrophilic peptides. This finding may offer new clues for the design of therapeutic agents against different types of amyloidosis.