Abstract
Small oligomers formed early along human islet amyloid polypeptide (hIAPP) aggregation is responsible for the cell death in Type II diabetes. The epigallocatechin gallate (EGCG), a green tea extract, was found to inhibit hIAPP fibrillation. However, the inhibition mechanism and the conformational distribution of the smallest hIAPP oligomer – dimer are mostly unknown. Herein, we performed extensive replica exchange molecular dynamic simulations on hIAPP dimer with and without EGCG molecules. Extended hIAPP dimer conformations, with a collision cross section value similar to that observed by ion mobility-mass spectrometry, were observed in our simulations. Notably, these dimers adopt a three-stranded antiparallel β-sheet and contain the previously reported β-hairpin amyloidogenic precursor. We find that EGCG binding strongly blocks both the inter-peptide hydrophobic and aromatic-stacking interactions responsible for inter-peptide β-sheet formation and intra-peptide interaction crucial for β-hairpin formation, thus abolishes the three-stranded β-sheet structures and leads to the formation of coil-rich conformations. Hydrophobic, aromatic-stacking, cation-π and hydrogen-bonding interactions jointly contribute to the EGCG-induced conformational shift. This study provides, on atomic level, the conformational ensemble of hIAPP dimer and the molecular mechanism by which EGCG inhibits hIAPP aggregation.
Highlights
Small oligomers formed early along human islet amyloid polypeptide aggregation is responsible for the cell death in Type II diabetes
Amyloid fibrillar deposits formed by the aggregation of human islet amyloid polypeptide are pathological hallmark of type II diabetes1,2. hIAPP is a 37-residue peptide co-secreted with insulin by islet β-cell[3,4] Increasing evidence shows that the low molecular weight soluble oligomers formed in the early stage of hIAPP aggregation are the most neurotoxic agents[5,6,7,8]
By performing 360-ns all-atom explicit-solvent replica-exchange molecular dynamics (REMD) simulations on hIAPP dimer in the absence and presence of epigallocatechin gallate (EGCG) molecules, we have investigated the conformational ensembles of hIAPP dimer and the interaction mechanism between EGCG and hIAPP molecules
Summary
Small oligomers formed early along human islet amyloid polypeptide (hIAPP) aggregation is responsible for the cell death in Type II diabetes. This study provides, on atomic level, the conformational ensemble of hIAPP dimer and the molecular mechanism by which EGCG inhibits hIAPP aggregation. HIAPP monomer[20,21,22,23,24,25,26] and the structural stability of preformed IAPP protofibrils[27,28] Both implicit- and explicit-solvent REMD studies suggested that the monomeric hIAPP can transiently populate extended β-hairpin conformations[20,21,22,23,24,25,26], and this β-hairpin was proposed to be the amyloidogenic precursor[21,22]. Several research groups have investigated the mechanism by which EGCG molecules inhibit the aggregation of Alzheimers amyloid-β(Aβ) peptide[34,35] and the action modes of EGCG in remodeling the preformed hIAPP protofibrils[36], the influence of EGCG molecules on hIAPP aggregation has not been explored at atomic-level details
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