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Formation and Growth of Oligomers: A Monte Carlo Study of an Amyloid Tau Fragment

Li, Da-Wei; Mohanty, Sandipan; Irbäck, Anders LU and Huo, Shuanghong (2008) In PLoS Computational Biology 4(12).
Abstract
Small oligomers formed early in the process of amyloid fibril formation may be the major toxic species in Alzheimer's disease. We investigate the early stages of amyloid aggregation for the tau fragment AcPHF6 (Ac-VQIVYK-NH2) using an implicit solvent all-atom model and extensive Monte Carlo simulations of 12, 24, and 36 chains. A variety of small metastable aggregates form and dissolve until an aggregate of a critical size and conformation arises. However, the stable oligomers, which are beta-sheet-rich and feature many hydrophobic contacts, are not always growth-ready. The simulations indicate instead that these supercritical oligomers spend a lengthy period in equilibrium in which considerable reorganization takes place accompanied by... (More)
Small oligomers formed early in the process of amyloid fibril formation may be the major toxic species in Alzheimer's disease. We investigate the early stages of amyloid aggregation for the tau fragment AcPHF6 (Ac-VQIVYK-NH2) using an implicit solvent all-atom model and extensive Monte Carlo simulations of 12, 24, and 36 chains. A variety of small metastable aggregates form and dissolve until an aggregate of a critical size and conformation arises. However, the stable oligomers, which are beta-sheet-rich and feature many hydrophobic contacts, are not always growth-ready. The simulations indicate instead that these supercritical oligomers spend a lengthy period in equilibrium in which considerable reorganization takes place accompanied by exchange of chains with the solution. Growth competence of the stable oligomers correlates with the alignment of the strands in the beta-sheets. The larger aggregates seen in our simulations are all composed of two twisted beta-sheets, packed against each other with hydrophobic side chains at the sheet-sheet interface. These beta-sandwiches show similarities with the proposed steric zipper structure for PHF6 fibrils but have a mixed parallel/antiparallel beta-strand organization as opposed to the parallel organization found in experiments on fibrils. Interestingly, we find that the fraction of parallel beta-sheet structure increases with aggregate size. We speculate that the reorganization of the beta-sheets into parallel ones is an important rate-limiting step in the formation of PHF6 fibrils. (Less)
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organization
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type
Contribution to journal
publication status
published
subject
in
PLoS Computational Biology
volume
4
issue
12
publisher
Public Library of Science
external identifiers
  • wos:000263923800017
  • scopus:58149174069
ISSN
1553-7358
DOI
10.1371/journal.pcbi.1000238
language
English
LU publication?
yes
id
ba7949df-31b7-4eb8-bcf0-f072a82ec63e (old id 1375169)
date added to LUP
2009-05-08 14:08:56
date last changed
2017-08-20 03:31:01
@article{ba7949df-31b7-4eb8-bcf0-f072a82ec63e,
  abstract     = {Small oligomers formed early in the process of amyloid fibril formation may be the major toxic species in Alzheimer's disease. We investigate the early stages of amyloid aggregation for the tau fragment AcPHF6 (Ac-VQIVYK-NH2) using an implicit solvent all-atom model and extensive Monte Carlo simulations of 12, 24, and 36 chains. A variety of small metastable aggregates form and dissolve until an aggregate of a critical size and conformation arises. However, the stable oligomers, which are beta-sheet-rich and feature many hydrophobic contacts, are not always growth-ready. The simulations indicate instead that these supercritical oligomers spend a lengthy period in equilibrium in which considerable reorganization takes place accompanied by exchange of chains with the solution. Growth competence of the stable oligomers correlates with the alignment of the strands in the beta-sheets. The larger aggregates seen in our simulations are all composed of two twisted beta-sheets, packed against each other with hydrophobic side chains at the sheet-sheet interface. These beta-sandwiches show similarities with the proposed steric zipper structure for PHF6 fibrils but have a mixed parallel/antiparallel beta-strand organization as opposed to the parallel organization found in experiments on fibrils. Interestingly, we find that the fraction of parallel beta-sheet structure increases with aggregate size. We speculate that the reorganization of the beta-sheets into parallel ones is an important rate-limiting step in the formation of PHF6 fibrils.},
  articleno    = {e1000238},
  author       = {Li, Da-Wei and Mohanty, Sandipan and Irbäck, Anders and Huo, Shuanghong},
  issn         = {1553-7358},
  language     = {eng},
  number       = {12},
  publisher    = {Public Library of Science},
  series       = {PLoS Computational Biology},
  title        = {Formation and Growth of Oligomers: A Monte Carlo Study of an Amyloid Tau Fragment},
  url          = {http://dx.doi.org/10.1371/journal.pcbi.1000238},
  volume       = {4},
  year         = {2008},
}