Conformational Ensemble of hIAPP Dimer: Insight into the Molecular Mechanism by which a Green Tea Extract inhibits hIAPP Aggregation.
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.
Key Laboratory for Computational Physical Sciences (MOE), State Key Laboratory of Surface Physics, and Department of Physics, Fudan University, Shanghai 200433, China.|College of Physical Science and Technology, Guangxi Normal University, 15 Yucai Road, Guilin, 541004, China.
Yuxiang
Y
Mo
Key Laboratory for Computational Physical Sciences (MOE), State Key Laboratory of Surface Physics, and Department of Physics, Fudan University, Shanghai 200433, China.
Jiangtao
J
Lei
Key Laboratory for Computational Physical Sciences (MOE), State Key Laboratory of Surface Physics, and Department of Physics, Fudan University, Shanghai 200433, China.
Yunxiang
Y
Sun
College of Physical Education and Training, Shanghai University of Sport, 399 Changhai Road, Shanghai 200438, China.
Qingwen
Q
Zhang
Key Laboratory for Computational Physical Sciences (MOE), State Key Laboratory of Surface Physics, and Department of Physics, Fudan University, Shanghai 200433, China.
Guanghong
G
Wei
D002392:Catechin / Q000031:analogs & derivatives* / Q000737:chemistry; D006801:Humans; D013058:Mass Spectrometry; D056004:Molecular Dynamics Simulation; D010936:Plant Extracts / Q000737:chemistry*; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8 / Q000737:chemistry*; D013662:Tea / Q000737:chemistry*
D010936:Plant Extracts; D013662:Tea; D002392:Catechin; C045651:epigallocatechin gallate; C102889:PTPRN2 protein, human; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8