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How the amyloid-β peptide and membranes affect each other: An extensive simulation study

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How the amyloid-β peptide and membranes affect each other : An extensive simulation study. / Poojari, Chetan; Kukol, A.; Strodel, Birgit.

In: Biochimica et Biophysica Acta - Biomembranes, Vol. 1828, No. 2, 327-339, 02.2013.

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@article{256cfa2fb8c1466499208811d872090a,
title = "How the amyloid-β peptide and membranes affect each other: An extensive simulation study",
abstract = "The etiology of Alzheimer's disease is thought to be linked to interactions between amyloid-β (Aβ) and neural cell membranes, causing membrane disruption and increased ion conductance. The effects of Aβ on lipid behavior have been characterized experimentally, but structural and causal details are lacking. We used atomistic molecular dynamics simulations totaling over 6μs in simulation time to investigate the behavior of Aβ(42) in zwitterionic and anionic lipid bilayers. We simulated transmembrane β-sheets (monomer and tetramer) resulting from a global optimization study and a helical structure obtained from an NMR study. In all simulations Aβ(42) remained embedded in the bilayer. It was found that the surface charge and the lipid tail type are determinants for transmembrane stability of Aβ(42) with zwitterionic surfaces and unsaturated lipids promoting stability. From the considered structures, the β-sheet tetramer is most stable as a result of interpeptide interactions. We performed an in-depth analysis of the translocation of water in the Aβ(42)-bilayer systems. We observed that this process is generally fast (within a few nanoseconds) yet generally slower than in the peptide-free bilayers. It is mainly governed by the lipid type, simulation temperature and Aβ(42) conformation. The rate limiting step is the permeation through the hydrophobic core, where interactions between Aβ(42) and permeating H(2)Omolecules slow the translocation process. The β-sheet tetramer allows more water molecules to pass through the bilayer compared to monomeric Aβ, allowing us to conclude that the experimentally observed permeabilization of membranes must be due to membrane-bound Aβ oligomers, and not monomers.",
author = "Chetan Poojari and A. Kukol and Birgit Strodel",
note = "Copyright {\textcopyright} 2012. Published by Elsevier B.V.",
year = "2013",
month = feb,
doi = "10.1016/j.bbamem.2012.09.001",
language = "English",
volume = "1828",
journal = "Biochimica et Biophysica Acta - Biomembranes",
issn = "0005-2736",
publisher = "Elsevier",
number = "2",

}

RIS

TY - JOUR

T1 - How the amyloid-β peptide and membranes affect each other

T2 - An extensive simulation study

AU - Poojari, Chetan

AU - Kukol, A.

AU - Strodel, Birgit

N1 - Copyright © 2012. Published by Elsevier B.V.

PY - 2013/2

Y1 - 2013/2

N2 - The etiology of Alzheimer's disease is thought to be linked to interactions between amyloid-β (Aβ) and neural cell membranes, causing membrane disruption and increased ion conductance. The effects of Aβ on lipid behavior have been characterized experimentally, but structural and causal details are lacking. We used atomistic molecular dynamics simulations totaling over 6μs in simulation time to investigate the behavior of Aβ(42) in zwitterionic and anionic lipid bilayers. We simulated transmembrane β-sheets (monomer and tetramer) resulting from a global optimization study and a helical structure obtained from an NMR study. In all simulations Aβ(42) remained embedded in the bilayer. It was found that the surface charge and the lipid tail type are determinants for transmembrane stability of Aβ(42) with zwitterionic surfaces and unsaturated lipids promoting stability. From the considered structures, the β-sheet tetramer is most stable as a result of interpeptide interactions. We performed an in-depth analysis of the translocation of water in the Aβ(42)-bilayer systems. We observed that this process is generally fast (within a few nanoseconds) yet generally slower than in the peptide-free bilayers. It is mainly governed by the lipid type, simulation temperature and Aβ(42) conformation. The rate limiting step is the permeation through the hydrophobic core, where interactions between Aβ(42) and permeating H(2)Omolecules slow the translocation process. The β-sheet tetramer allows more water molecules to pass through the bilayer compared to monomeric Aβ, allowing us to conclude that the experimentally observed permeabilization of membranes must be due to membrane-bound Aβ oligomers, and not monomers.

AB - The etiology of Alzheimer's disease is thought to be linked to interactions between amyloid-β (Aβ) and neural cell membranes, causing membrane disruption and increased ion conductance. The effects of Aβ on lipid behavior have been characterized experimentally, but structural and causal details are lacking. We used atomistic molecular dynamics simulations totaling over 6μs in simulation time to investigate the behavior of Aβ(42) in zwitterionic and anionic lipid bilayers. We simulated transmembrane β-sheets (monomer and tetramer) resulting from a global optimization study and a helical structure obtained from an NMR study. In all simulations Aβ(42) remained embedded in the bilayer. It was found that the surface charge and the lipid tail type are determinants for transmembrane stability of Aβ(42) with zwitterionic surfaces and unsaturated lipids promoting stability. From the considered structures, the β-sheet tetramer is most stable as a result of interpeptide interactions. We performed an in-depth analysis of the translocation of water in the Aβ(42)-bilayer systems. We observed that this process is generally fast (within a few nanoseconds) yet generally slower than in the peptide-free bilayers. It is mainly governed by the lipid type, simulation temperature and Aβ(42) conformation. The rate limiting step is the permeation through the hydrophobic core, where interactions between Aβ(42) and permeating H(2)Omolecules slow the translocation process. The β-sheet tetramer allows more water molecules to pass through the bilayer compared to monomeric Aβ, allowing us to conclude that the experimentally observed permeabilization of membranes must be due to membrane-bound Aβ oligomers, and not monomers.

U2 - 10.1016/j.bbamem.2012.09.001

DO - 10.1016/j.bbamem.2012.09.001

M3 - Article

C2 - 22975281

VL - 1828

JO - Biochimica et Biophysica Acta - Biomembranes

JF - Biochimica et Biophysica Acta - Biomembranes

SN - 0005-2736

IS - 2

M1 - 327-339

ER -