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Comparing the folding free-energy landscapes of Abeta42 variants with different aggregation properties.

Mitternacht, Simon LU ; Staneva, Iskra LU ; Härd, Torleif and Irbäck, Anders LU (2010) In Proteins 78(12). p.2600-2608
Abstract
The properties of the amyloid-beta peptide that lead to aggregation associated with Alzheimer's disease are not fully understood. This study aims at identifying conformational differences among four variants of full-length Abeta42 that are known to display very different aggregation properties. By extensive all-atom Monte Carlo simulations, we find that a variety of beta-sheet structures with distinct turns are readily accessible for full-length Abeta42. In the simulations, wild type (WT) Abeta42 preferentially populates two major classes of conformations, either extended with high beta-sheet content or more compact with lower beta-sheet content. The three mutations studied alter the balance between these classes. Strong mutational effects... (More)
The properties of the amyloid-beta peptide that lead to aggregation associated with Alzheimer's disease are not fully understood. This study aims at identifying conformational differences among four variants of full-length Abeta42 that are known to display very different aggregation properties. By extensive all-atom Monte Carlo simulations, we find that a variety of beta-sheet structures with distinct turns are readily accessible for full-length Abeta42. In the simulations, wild type (WT) Abeta42 preferentially populates two major classes of conformations, either extended with high beta-sheet content or more compact with lower beta-sheet content. The three mutations studied alter the balance between these classes. Strong mutational effects are observed in a region centered at residues 23-26, where WT Abeta42 tends to form a turn. The aggregation-accelerating E22G mutation associated with early onset of Alzheimer's disease makes this turn region conformationally more diverse, whereas the aggregation-decelerating F20E mutation has the reverse effect, and the E22G/I31E mutation reduces the turn population. Comparing results for the four Abeta42 variants, we identify specific conformational properties of residues 23-26 that might play a key role in aggregation. Proteins 2010. (c) 2010 Wiley-Liss, Inc. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
mutations, amyloid-beta, all atom, implicit solvent, Monte Carlo, J-coupling constants, chemical shifts
in
Proteins
volume
78
issue
12
pages
2600 - 2608
publisher
John Wiley & Sons
external identifiers
  • wos:000280822000003
  • pmid:20589631
  • scopus:77955790562
ISSN
0887-3585
DOI
10.1002/prot.22775
language
English
LU publication?
yes
id
5a663388-83f2-4c4f-8e46-9427885d1b59 (old id 1645446)
date added to LUP
2010-08-05 18:22:08
date last changed
2018-05-29 10:05:14
@article{5a663388-83f2-4c4f-8e46-9427885d1b59,
  abstract     = {The properties of the amyloid-beta peptide that lead to aggregation associated with Alzheimer's disease are not fully understood. This study aims at identifying conformational differences among four variants of full-length Abeta42 that are known to display very different aggregation properties. By extensive all-atom Monte Carlo simulations, we find that a variety of beta-sheet structures with distinct turns are readily accessible for full-length Abeta42. In the simulations, wild type (WT) Abeta42 preferentially populates two major classes of conformations, either extended with high beta-sheet content or more compact with lower beta-sheet content. The three mutations studied alter the balance between these classes. Strong mutational effects are observed in a region centered at residues 23-26, where WT Abeta42 tends to form a turn. The aggregation-accelerating E22G mutation associated with early onset of Alzheimer's disease makes this turn region conformationally more diverse, whereas the aggregation-decelerating F20E mutation has the reverse effect, and the E22G/I31E mutation reduces the turn population. Comparing results for the four Abeta42 variants, we identify specific conformational properties of residues 23-26 that might play a key role in aggregation. Proteins 2010. (c) 2010 Wiley-Liss, Inc.},
  author       = {Mitternacht, Simon and Staneva, Iskra and Härd, Torleif and Irbäck, Anders},
  issn         = {0887-3585},
  keyword      = {mutations,amyloid-beta,all atom,implicit solvent,Monte Carlo,J-coupling constants,chemical shifts},
  language     = {eng},
  number       = {12},
  pages        = {2600--2608},
  publisher    = {John Wiley & Sons},
  series       = {Proteins},
  title        = {Comparing the folding free-energy landscapes of Abeta42 variants with different aggregation properties.},
  url          = {http://dx.doi.org/10.1002/prot.22775},
  volume       = {78},
  year         = {2010},
}