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000012607 0247_ $$2pmid$$apmid:20822103
000012607 0247_ $$2DOI$$a10.1021/ja103725c
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000012607 084__ $$2WoS$$aChemistry, Multidisciplinary
000012607 1001_ $$0P:(DE-Juel1)132024$$aStrodel, B.$$b0$$uFZJ
000012607 245__ $$aTransmembrane Structures for Alzheimer’s Aß1-42 Oligomers
000012607 260__ $$aWashington, DC$$bAmerican Chemical Society$$c2010
000012607 300__ $$a13300 - 13312
000012607 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article
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000012607 440_0 $$023404$$aJournal of the American Chemical Society$$v132$$x0002-7863$$y38
000012607 500__ $$aB.S. gratefully acknowledges the Julich Supercomputing Centre for providing and maintaining the computing resources used in this work. C.S.W. thanks the EPSRC for financial support.
000012607 520__ $$aWe model oligomers of the Alzheimer's amyloid β-peptide Aβ(1-42) in an implicit membrane to obtain insight into the mechanism of amyloid toxicity. It has been suggested that Aβ oligomers are the toxic species, causing membrane disruption in neuronal cells due to pore formation. We use basin-hopping global optimization to identify the most stable structures for the Aβ(1-42) peptide monomer and small oligomers up to the octamer inserted into a lipid bilayer. To improve the efficacy of the basin-hopping approach, we introduce a basin-hopping parallel tempering scheme and an oligomer generation procedure. The most stable membrane-spanning structure for the monomer is identified as a β-sheet, which exhibits the typical strand-turn-strand motif observed in NMR experiments. We find ordered β-sheets for the dimer to the hexamer, whereas for the octamer, we observe that the ordered structures separate into distinct tetrameric units that are rotated or shifted with respect to each other. This effect leads to an increase in favorable peptide-peptide interactions, thereby stabilizing the membrane-inserted octamer. On the basis of these results, we suggest that Aβ pores may consist of tetrameric and hexameric β-sheet subunits. These Aβ pore models are consistent with the results of biophysical and biochemical experiments.
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000012607 650_2 $$2MeSH$$aAmyloid beta-Peptides: chemistry
000012607 650_2 $$2MeSH$$aBiopolymers: chemistry
000012607 650_2 $$2MeSH$$aModels, Molecular
000012607 650_2 $$2MeSH$$aNuclear Magnetic Resonance, Biomolecular
000012607 650_2 $$2MeSH$$aPeptide Fragments: chemistry
000012607 650_2 $$2MeSH$$aProtein Conformation
000012607 650_2 $$2MeSH$$aThermodynamics
000012607 650_7 $$00$$2NLM Chemicals$$aAmyloid beta-Peptides
000012607 650_7 $$00$$2NLM Chemicals$$aBiopolymers
000012607 650_7 $$00$$2NLM Chemicals$$aPeptide Fragments
000012607 650_7 $$00$$2NLM Chemicals$$aamyloid beta-protein (1-42)
000012607 650_7 $$2WoSType$$aJ
000012607 7001_ $$0P:(DE-HGF)0$$aLee, J.W.L.$$b1
000012607 7001_ $$0P:(DE-HGF)0$$aWhittleston, C.S.$$b2
000012607 7001_ $$0P:(DE-HGF)0$$aWales, D.J.$$b3
000012607 773__ $$0PERI:(DE-600)1472210-0$$a10.1021/ja103725c$$gVol. 132, p. 13300 - 13312$$p13300 - 13312$$q132<13300 - 13312$$tJournal of the American Chemical Society$$v132$$x0002-7863$$y2010
000012607 8567_ $$uhttp://dx.doi.org/10.1021/ja103725c
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000012607 915__ $$0StatID:(DE-HGF)0010$$aJCR/ISI refereed
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