Abstract
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.
Highlights
Human islet amyloid polypeptide is an intrinsically disordered protein and plays a significant role in the progression of type 2 diabetes (Cooper et al, 1987). human islet amyloid polypeptide (hIAPP) has a high propensity to form amyloid aggregates (Larson and Miranker, 2004; Brender et al, 2010)
The three regions are reported to be the amyloidogenic regions in many experimental studies (Jaikaran et al, 2001; Nielsen et al, 2009; FIGURE 1 | Influence of C60 and C60(OH)8 on the secondary structures of hIAPP dimer
The probabilities of short β-sheets decrease dramatically in the presence of C60, while their change becomes less prominent in hIAPP dimer + C60(OH)8 system
Summary
Human islet amyloid polypeptide (hIAPP) is an intrinsically disordered protein and plays a significant role in the progression of type 2 diabetes (Cooper et al, 1987). hIAPP has a high propensity to form amyloid aggregates (Larson and Miranker, 2004; Brender et al, 2010). Human islet amyloid polypeptide (hIAPP) is an intrinsically disordered protein and plays a significant role in the progression of type 2 diabetes (Cooper et al, 1987). Amyloid deposits derived from hIAPP are observed in human islet extracellular space in type 2 diabetes and the formation of intracellular hIAPP oligomers may conduce to β-cell loss in Type 2 diabetes (Haataja et al, 2008). Finding an Pristine/Hydroxylated Fullerene Inhibit hIAPP Aggregation effective inhibitor of hIAPP aggregation is a crucial step for reducing islet β-cells death and the development of drugs against Type 2 diabetes. Ke et al demonstrated that nanomaterials can inhibit hIAPP aggregation and reduce the toxicity in silico, in vitro, and in vivo (Wang et al, 2018; Faridi et al, 2019; Ke et al, 2019)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
