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

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 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.

Dissecting the Supramolecular Dispersion of Fullerenes by Proteins/Peptides: Amino Acid Ranking and Driving Forces for Binding to C60

“…If we consider the extended π-system of the fullerene, it is not surprising that aromatic amino acids such as tryptophan, tyrosine, phenylalanine, and histidine interacted the most with it ( Figure 3 ) [ 20 , 24 , 33 , 34 , 35 , 39 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ]. In particular, Trp exhibited the largest value of binding energy among the twenty proteinogenic amino acids.…”

“…In protein/peptide-fullerene complexes, several aliphatic residues are usually part of the C 60 binding pocket and contribute to binding [ 33 , 35 , 49 ]. Hydrophobic interactions can be established with methionine, valine, isoleucine, leucine, proline, alanine, and glycine ( Figure 6 ).…”

Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

“…GQDs for in vivo mitigation of T2D amyloidosis.By combining all-atom REMD and MD simulations, AFM and TEM images, ThT and cell toxicity assays, Mo et al[957][958][959] examined the influences of hydroxylated carbon nanotubes and fullerenes on the fibrillization of hIAPP. REMD and MD simulations demonstrated that both CNT-OHs and C60OHs not only suppress the formation of β-sheet and β-hairpin-containing amyloidogenic precursor of hIAPP, but also remodel or disassemble preformed hIAPP protofibrils/fibrils.…”

Interactive Mechanism of Potential Inhibitors with Glycosyl for SARS-CoV-2 by Molecular Dynamics Simulation

“…Our analysis shows that the average CSA values are 489.48 Å 2 in the S_RBD in the presence of Cefuroxime system, 617.884 Å 2 in the S_RBD in the presence of Erythromycin system, 560.749 Å 2 in the S_RBD in the presence of Lincomycin system, and 546.891 Å 2 in the S_RBD with Ofloxacin system, respectively, as described in Figure 4C. These demonstrate a comparatively stronger binding affinity between S_RBD and Erythromycin/Lincomycin than the other systems [53]. The CSA value of Erythromycin and S_RBD is even larger, because the molecular weight and the surface of Erythromycin is larger than other molecules.…”