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@ARTICLE{Strodel:12607,
author = {Strodel, B. and Lee, J.W.L. and Whittleston, C.S. and
Wales, D.J.},
title = {{T}ransmembrane {S}tructures for {A}lzheimer’s {A}ß1-42
{O}ligomers},
journal = {Journal of the American Chemical Society},
volume = {132},
issn = {0002-7863},
address = {Washington, DC},
publisher = {American Chemical Society},
reportid = {PreJuSER-12607},
pages = {13300 - 13312},
year = {2010},
note = {B.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.},
abstract = {We 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.},
keywords = {Amyloid beta-Peptides: chemistry / Biopolymers: chemistry /
Models, Molecular / Nuclear Magnetic Resonance, Biomolecular
/ Peptide Fragments: chemistry / Protein Conformation /
Thermodynamics / Amyloid beta-Peptides (NLM Chemicals) /
Biopolymers (NLM Chemicals) / Peptide Fragments (NLM
Chemicals) / amyloid beta-protein (1-42) (NLM Chemicals) / J
(WoSType)},
cin = {ISB-3},
ddc = {540},
cid = {I:(DE-Juel1)VDB942},
pnm = {Funktion und Dysfunktion des Nervensystems / BioSoft:
Makromolekulare Systeme und biologische
Informationsverarbeitung},
pid = {G:(DE-Juel1)FUEK409 / G:(DE-Juel1)FUEK505},
shelfmark = {Chemistry, Multidisciplinary},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:20822103},
UT = {WOS:000282304000055},
doi = {10.1021/ja103725c},
url = {https://juser.fz-juelich.de/record/12607},
}