Pristine and Hydroxylated Fullerenes Prevent the Aggregation of Human Islet Amyloid Polypeptide and Display Different...

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.