Journal
SCIENTIFIC REPORTS
Volume 6, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/srep33076
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Funding
- NSF of China [11274075, 11674065]
- MOST of China [2016YFA0501702]
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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 beta-sheet and contain the previously reported beta-hairpin amyloidogenic precursor. We find that EGCG binding strongly blocks both the inter-peptide hydrophobic and aromatic-stacking interactions responsible for inter-peptide beta-sheet formation and intra-peptide interaction crucial for beta-hairpin formation, thus abolishes the three-stranded beta-sheet structures and leads to the formation of coil-rich conformations. Hydrophobic, aromatic-stacking, cation-p 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.
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