Destabilization of Human Islet Amyloid Polypeptide Fibrils by Charged Graphene Quantum Dots: A Molecular Dynamics Investigation with Implications for Nanomedicine

Abstract

Human islet amyloid polypeptide (hIAPP) is the major component of the amyloid deposited in the pancreas of patients with type 2 diabetes mellitus. Its aggregation and consequent production of intermediates are believed to be responsible for its cytotoxicity and pathological processes. Recently, graphene quantum dots (GQDs) are proved to effectively inhibit a range of amyloid deposits. This work focuses on the influence of the charged GQDs on hIAPP inhibition. Microsecond all-atom molecular dynamics simulations in explicit water were performed to study the influence of charged GQDs on the structural stability of hIAPP fibril. GQDs were found to be able to destabilize the hIAPP fibril and reduce the β-sheet content. The stability of the hydrophobic core was greatly disturbed, and the hydrogen bond formation at protofibril interfaces was also hindered. The negatively and positively charged GQDs have different binding sites, dynamics, and interactions at hIAPP fibril, which is dominated by electrostatic interaction and assisted by π–π stacking, salt bridge, and hydrogen bonding interactions. The π–π stacking between GQDs and hIAPP may be influenced by the electrostatic interaction in a facilitative or competitive manner. In addition, the negatively charged GQD is suggested to be a better candidate of amyloid inhibition than the positively charged one in disruptive effect, binding modes, and binding intensity. These findings may provide useful perspectives for the design of nanomedicine for amyloid inhibition and are helpful to the development of diagnosis and screening nanotechnology for neurodegenerative diseases