Dynamics of metastable β-hairpin structures in the folding nucleus of amyloid β-protein.

The Journal of Physical Chemistry. B
Luis CruzBrigita Urbanc

Abstract

The amyloid β-protein (Aβ), which is present predominately as a 40- or 42-residue peptide, is postulated to play a seminal role in the pathogenesis of Alzheimer's disease (AD). Folding of the Aβ(21-30) decapeptide region is a critical step in the aggregation of Aβ. We report results of constant temperature all-atom molecular dynamics simulations in explicit water of the dynamics of monomeric Aβ(21-30) and its Dutch [Glu22Gln], Arctic [Glu22Gly], and Iowa [Asp23Asn] isoforms that are associated with familial forms of cerebral amyloid angiopathy and AD. The simulations revealed a variety of loop conformers that exhibited a hydrogen bond network involving the Asp23 and Ser26 amino acids. A population of conformers, not part of the loop population, was found to form metastable β-hairpin structures with the highest probability in the Iowa mutant. At least three β-hairpin structures were found that differed in their hydrogen bonding register, average number of backbone hydrogen bonds, and lifetimes. Analysis revealed that the Dutch mutant had the longest β-hairpin lifetime (≥500 ns), closely followed by the Iowa mutant (≈500 ns). Aβ(21-30) and the Arctic mutant had significantly lower lifetimes (≈200 ns). Hydrophobic packing of side ...Continue Reading

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Citations

Mar 13, 2014·The Journal of Physical Chemistry. B·J Srinivasa RaoLuis Cruz
Dec 3, 2015·Journal of Chemical Information and Modeling·Micholas Dean SmithLuis R Cruz Cruz
Aug 19, 2014·Protein Science : a Publication of the Protein Society·Jitka PetrlovaAnders Irbäck
Aug 21, 2013·Proceedings of the National Academy of Sciences of the United States of America·Ying ZhangMichael L Gross
May 9, 2016·Journal of Biological Physics·Matjaž ŽganecBrigita Urbanc
Jun 4, 2014·Physical Chemistry Chemical Physics : PCCP·Micholas Dean SmithLuis Cruz
Jul 20, 2014·The Journal of Biological Chemistry·Massimo MessaMario Salmona
May 20, 2020·Chembiochem : a European Journal of Chemical Biology·Jevgenij A Raskatov
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Jan 24, 2015·The Journal of Biological Chemistry·Hannah A DaviesDavid A Middleton
Aug 28, 2020·The Journal of Physical Chemistry. B·Dilnoza B AmirkulovaAndrew D White
Nov 23, 2013·The Journal of Physical Chemistry. B·Micholas Dean Smith, Luis Cruz
May 17, 2013·The Journal of Physical Chemistry. B·Micholas Dean Smith, Luis Cruz
Jan 15, 2013·Journal of Chemical Theory and Computation·Hyunbum JangRuth Nussinov
Mar 20, 2015·Chemical Reviews·Jessica Nasica-LabouzePhilippe Derreumaux
May 29, 2015·Journal of Chemical Information and Modeling·Liang XuBuyong Ma

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