TY  - JOUR
AU  - Strodel, B.
AU  - Lee, J.W.L.
AU  - Whittleston, C.S.
AU  - Wales, D.J.
TI  - Transmembrane Structures for Alzheimer’s Aß1-42 Oligomers
JO  - Journal of the American Chemical Society
VL  - 132
SN  - 0002-7863
CY  - Washington, DC
PB  - American Chemical Society
M1  - PreJuSER-12607
SP  - 13300 - 13312
PY  - 2010
N1  - 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.
AB  - 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.
KW  - Amyloid beta-Peptides: chemistry
KW  - Biopolymers: chemistry
KW  - Models, Molecular
KW  - Nuclear Magnetic Resonance, Biomolecular
KW  - Peptide Fragments: chemistry
KW  - Protein Conformation
KW  - Thermodynamics
KW  - Amyloid beta-Peptides (NLM Chemicals)
KW  - Biopolymers (NLM Chemicals)
KW  - Peptide Fragments (NLM Chemicals)
KW  - amyloid beta-protein (1-42) (NLM Chemicals)
KW  - J (WoSType)
LB  - PUB:(DE-HGF)16
C6  - pmid:20822103
UR  - <Go to ISI:>//WOS:000282304000055
DO  - DOI:10.1021/ja103725c
UR  - https://juser.fz-juelich.de/record/12607
ER  -