AUTHOR=Bai Cuiqin , Lao Zenghui , Chen Yujie , Tang Yiming , Wei Guanghong 

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

JOURNAL=Frontiers in Chemistry

VOLUME=8

YEAR=2020

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2020.00051

DOI=10.3389/fchem.2020.00051

ISSN=2296-2646

ABSTRACT=<p>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<sub>60</sub> (a model system of hydrophobic nanoparticle) and C<sub>60</sub>(OH)<sub>8</sub> (a hydroxylated fullerene) on hIAPP aggregation remain unknown. In this study, we investigate the influences of pristine fullerene C<sub>60</sub> and hydroxylated C<sub>60</sub> 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<sub>60</sub> and C<sub>60</sub>(OH)<sub>8</sub> 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<sub>60</sub> is mainly via hydrophobic and aromatic-stacking interactions, while the prevention of hIAPP aggregation by C<sub>60</sub>(OH)<sub>8</sub> is mostly through collective hydrogen bonding and aromatic-stacking interactions. Conventional MD simulations indicate that both C<sub>60</sub> and C<sub>60</sub>(OH)<sub>8</sub> weaken the interactions within hIAPP protofibril and disrupt the β-sheet structure. These results provide mechanistic insights into the possible inhibitory mechanism of C<sub>60</sub> and C<sub>60</sub>(OH)<sub>8</sub> toward hIAPP aggregation, and they are of great reference value for the screening of potent amyloid inhibitors.</p>