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Monte Carlo Study of the Formation and Conformational Properties of Dimers of Aβ42 Variants.

Mitternacht, Simon LU ; Staneva, Iskra LU ; Härd, Torleif and Irbäck, Anders LU (2011) In Journal of Molecular Biology 410(2). p.357-367
Abstract
Small soluble oligomers, as well as dimers in particular, of the amyloid β-peptide (Aβ) are believed to play an important pathological role in Alzheimer's disease. Here, we investigate the spontaneous dimerization of Aβ42, with 42 residues, by implicit solvent all-atom Monte Carlo simulations, for the wild-type peptide and the mutants F20E, E22G and E22G/I31E. The observed dimers of these variants share many overall conformational characteristics but differ in several aspects at a detailed level. In all four cases, the most common type of secondary structure is intramolecular antiparallel β-sheets. Parallel, in-register β-sheet structure, as in models for Aβ fibrils, is rare. The primary force driving the formation of dimers is hydrophobic... (More)
Small soluble oligomers, as well as dimers in particular, of the amyloid β-peptide (Aβ) are believed to play an important pathological role in Alzheimer's disease. Here, we investigate the spontaneous dimerization of Aβ42, with 42 residues, by implicit solvent all-atom Monte Carlo simulations, for the wild-type peptide and the mutants F20E, E22G and E22G/I31E. The observed dimers of these variants share many overall conformational characteristics but differ in several aspects at a detailed level. In all four cases, the most common type of secondary structure is intramolecular antiparallel β-sheets. Parallel, in-register β-sheet structure, as in models for Aβ fibrils, is rare. The primary force driving the formation of dimers is hydrophobic attraction. The conformational differences that we do see involve turns centered in the 20-30 region. The probability of finding turns centered in the 25-30 region, where there is a loop in Aβ fibrils, is found to increase upon dimerization and to correlate with experimentally measured rates of fibril formation for the different Aβ42 variants. Our findings hint at reorganization of this part of the molecule as a potentially critical step in Aβ aggregation. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
protein aggregation, amyloid, oligomerization, molecular simulation, all atom
in
Journal of Molecular Biology
volume
410
issue
2
pages
357 - 367
publisher
Elsevier
external identifiers
  • wos:000292783000013
  • pmid:21616081
  • scopus:79958710594
ISSN
1089-8638
DOI
10.1016/j.jmb.2011.05.014
language
English
LU publication?
yes
id
7d673569-f02e-41d0-9963-ad81d629e141 (old id 1972075)
date added to LUP
2011-06-10 16:24:04
date last changed
2017-11-19 03:49:49
@article{7d673569-f02e-41d0-9963-ad81d629e141,
  abstract     = {Small soluble oligomers, as well as dimers in particular, of the amyloid β-peptide (Aβ) are believed to play an important pathological role in Alzheimer's disease. Here, we investigate the spontaneous dimerization of Aβ42, with 42 residues, by implicit solvent all-atom Monte Carlo simulations, for the wild-type peptide and the mutants F20E, E22G and E22G/I31E. The observed dimers of these variants share many overall conformational characteristics but differ in several aspects at a detailed level. In all four cases, the most common type of secondary structure is intramolecular antiparallel β-sheets. Parallel, in-register β-sheet structure, as in models for Aβ fibrils, is rare. The primary force driving the formation of dimers is hydrophobic attraction. The conformational differences that we do see involve turns centered in the 20-30 region. The probability of finding turns centered in the 25-30 region, where there is a loop in Aβ fibrils, is found to increase upon dimerization and to correlate with experimentally measured rates of fibril formation for the different Aβ42 variants. Our findings hint at reorganization of this part of the molecule as a potentially critical step in Aβ aggregation.},
  author       = {Mitternacht, Simon and Staneva, Iskra and Härd, Torleif and Irbäck, Anders},
  issn         = {1089-8638},
  keyword      = {protein aggregation,amyloid,oligomerization,molecular simulation,all atom},
  language     = {eng},
  number       = {2},
  pages        = {357--367},
  publisher    = {Elsevier},
  series       = {Journal of Molecular Biology},
  title        = {Monte Carlo Study of the Formation and Conformational Properties of Dimers of Aβ42 Variants.},
  url          = {http://dx.doi.org/10.1016/j.jmb.2011.05.014},
  volume       = {410},
  year         = {2011},
}