Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/98369
Title: Acidic pH retards the fibrillization of human islet amyloid polypeptide due to electrostatic repulsion of histidines
Authors: Li, Yang
Xu, Weixin
Mu, Yuguang
Zhang, John Z. H.
Keywords: DRNTU::Science::Biological sciences
Issue Date: 2013
Source: Li, Y., Xu, W., Mu, Y., & Zhang, J. Z. H. (2013). Acidic pH retards the fibrillization of human islet amyloid polypeptide due to electrostatic repulsion of histidines. The Journal of Chemical Physics, 139(5), 055102.
Series/Report no.: The journal of chemical physics
Abstract: The human Islet Amyloid Polypeptide (hIAPP) is the major constituent of amyloid deposits in pancreatic islets of type-II diabetes. IAPP is secreted together with insulin from the acidic secretory granules at a low pH of approximately 5.5 to the extracellular environment at a neutral pH. The increased accumulation of extracellular hIAPP in diabetes indicates that changes in pH may promote amyloid formation. To gain insights and underlying mechanisms of the pH effect on hIAPP fibrillogenesis, all-atom molecular dynamics simulations in explicit solvent model were performed to study the structural properties of five hIAPP protofibrillar oligomers, under acidic and neutral pH, respectively. In consistent with experimental findings, simulation results show that acidic pH is not conducive to the structural stability of these oligomers. This provides a direct evidence for a recent experiment [L. Khemtemourian, E. Domenech, J. P. F. Doux, M. C. Koorengevel, and J. A. Killian, J. Am. Chem. Soc. 133, 15598 (2011)]10.1021/ja205007j, which suggests that acidic pH inhibits the fibril formation of hIAPP. In addition, a complementary coarse-grained simulation shows the repulsive electrostatic interactions among charged His18 residues slow down the dimerization process of hIAPP by twofold. Besides, our all-atom simulations reveal acidic pH mainly affects the local structure around residue His18 by destroying the surrounding hydrogen-bonding network, due to the repulsive interactions between protonated interchain His18 residues at acidic pH. It is also disclosed that the local interactions nearby His18 operating between adjacent β-strands trigger the structural transition, which gives hints to the experimental findings that the rate of hIAPP fibril formation and the morphologies of the fibrillar structures are strongly pH-dependent
URI: https://hdl.handle.net/10356/98369
http://hdl.handle.net/10220/13354
ISSN: 0021-9606
DOI: 10.1063/1.4817000
Rights: © 2013 AIP Publishing LLC. This paper was published in The Journal of Chemical Physics and is made available as an electronic reprint (preprint) with permission of AIP Publishing LLC. The paper can be found at the following official DOI: [http://dx.doi.org/10.1063/1.4817000]. One print or electronic copy may be made for personal use only. Systematic or multiple reproduction, distribution to multiple locations via electronic or other means, duplication of any material in this paper for a fee or for commercial purposes, or modification of the content of the paper is prohibited and is subject to penalties under law.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SBS Journal Articles

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