Description: Transmembrane Structures for Alzheimer’s Aß1-42 Oligomers

This title appears in the Scientific Report : 2010

Transmembrane Structures for Alzheimer’s Aß1-42 Oligomers

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-hop...

Personal Name(s):	Strodel, B.
	Lee, J.W.L. / Whittleston, C.S. / Wales, D.J.
Contributing Institute:	Strukturbiochemie; ISB-3
Published in:	Journal of the American Chemical Society, 132 (2010) S. 13300 - 13312
Imprint:	Washington, DC American Chemical Society 2010
Physical Description:	13300 - 13312
DOI:	10.1021/ja103725c
PubMed ID:	20822103
Document Type:	Journal Article
Research Program:	BioSoft: Makromolekulare Systeme und biologische Informationsverarbeitung Funktion und Dysfunktion des Nervensystems
Series Title:	Journal of the American Chemical Society 132
Subject (ZB):	Amyloid beta-Peptides: chemistry Biopolymers: chemistry Models, Molecular Nuclear Magnetic Resonance, Biomolecular Peptide Fragments: chemistry Protein Conformation Thermodynamics Amyloid beta-Peptides Biopolymers Peptide Fragments amyloid beta-protein (1-42) J
	Publikationsportal JuSER

Please use the identifier: http://dx.doi.org/10.1021/ja103725c in citations.

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.