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

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 C(60) (a model system of hydrophobic nanoparticle) and C(60)(OH)(8) (a hydroxylated fullerene) on hIAPP aggregation remain unknown. In this study, we investigate the influences of pristine fullerene C(60) and hydroxylated C(60) 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 C(60) and C(60)(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 C(60) is mainly via hydrophobic and aromatic-stacking interactions, while the prevention of hIAPP aggregation by C(60)(OH)(8) is mostly through collective hydrogen bonding and aromatic-stacking interactions. Conventional MD simulations indicate that both C(60) and C(60)(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 C(60) and C(60)(OH)(8) toward hIAPP aggregation, and they are of great reference value for the screening of potent amyloid inhibitors.