Structural Properties of Human IAPP Dimer in Membrane Environment Studied by All-Atom Molecular Dynamics Simulations

被引:20
作者
Liu, Na [1 ,2 ]
Duan, Mojie [1 ]
Yang, Minghui [1 ]
机构
[1] Chinese Acad Sci, Wuhan Inst Phys & Math, State Key Lab Magnet Resonance & Atom & Mol Phys, Key Lab Magnet Resonance Biol Syst,Natl Ctr Magne, Wuhan 430071, Hubei, Peoples R China
[2] Univ Chinese Acad Sci, Beijing 100049, Peoples R China
来源
SCIENTIFIC REPORTS | 2017年 / 7卷
基金
中国国家自然科学基金;
关键词
ISLET AMYLOID POLYPEPTIDE; ALPHA-HELICAL STATES; A-BETA; AMYLIN; PROTEIN; MECHANISM; AGGREGATION; PEPTIDES; FIBRILS; INSULIN;
D O I
10.1038/s41598-017-08504-x
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The aggregation of human islet amyloid polypeptide (hIAPP) can damage the membrane of the beta-cells in the pancreatic islets and induce type 2 diabetes (T2D). Growing evidences indicated that the major toxic species are small oligomers of IAPP. Due to the fast aggregation nature, it is hard to characterize the structures of IAPP oligomers by experiments, especially in the complex membrane environment. On the other side, molecular dynamics simulation can provide atomic details of the structure and dynamics of the aggregation of IAPP. In this study, all-atom bias-exchange metadynamics (BE-Meta) and unbiased molecular dynamics simulations were employed to study the structural properties of IAPP dimer in the membranes environments. A number of intermediates, including alpha-helical states, beta-sheet states, and fully disordered states, are identified. The formation of N-terminal beta-sheet structure is prior to the C-terminal beta-sheet structure towards the final fibril-like structures. The alpha-helical intermediates have lower propensity in the dimeric hIAPP and are off-pathway intermediates. The simulations also demonstrate that the beta-sheet intermediates induce more perturbation on the membrane than the alpha-helical and disordered states and thus pose higher disruption ability.
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页数:12
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