Protein aggregation, involving the formation of dimers, oligomers, and fibrils, is associated with many human diseases. Type 2 diabetes is one of the common amyloidosis and linked with the aggregation of human islet amyloid polypeptide (hIAPP). A series of nanoparticles are reported to be able to interact with proteins and enhance/inhibit protein aggregation. However, the effects of C₆₀ (a model system of hydrophobic nanoparticle) and C₆₀(OH)₈ (a hydroxylated fullerene) on hIAPP aggregation remain unknown. In this study, we investigate the influences of pristine fullerene C₆₀ and hydroxylated C₆₀ on the dimerization of hIAPP using molecular dynamics (MD) simulations. Extensive replica exchange molecular dynamics (REMD) simulations show that isolated hIAPP dimers adopt β-sheet structure containing the amyloid-precursor (β-hairpin). Both C₆₀ and C₆₀(OH)₈ notably inhibit the β-sheet formation of hIAPP dimer and induce the formation of collapsed disordered coil-rich conformations. Protein-nanoparticle interaction analyses reveal that the inhibition of hIAPP aggregation by C₆₀ is mainly via hydrophobic and aromatic-stacking interactions, while the prevention of hIAPP aggregation by C₆₀(OH)₈ is mostly through collective hydrogen bonding and aromatic-stacking interactions. Conventional MD simulations indicate that both C₆₀ and C₆₀(OH)₈ weaken the interactions within hIAPP protofibril and disrupt the β-sheet structure. These results provide mechanistic insights into the possible inhibitory mechanism of C₆₀ and C₆₀(OH)₈ toward hIAPP aggregation, and they are of great reference value for the screening of potent amyloid inhibitors.

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