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Local Unfolding and Aggregation Mechanisms of SOD1: A Monte Carlo Exploration.

Bille, Anna LU ; Jonsson, Sigurdur LU ; Akke, Mikael LU and Irbäck, Anders LU (2013) In The Journal of Physical Chemistry Part B 117(31). p.9194-9202
Abstract
Copper, zinc superoxide dismutase 1 (SOD1) is a ubiquitous homodimeric enzyme, whose misfolding and aggregation play a potentially key role in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). SOD1 aggregation is thought to be preceded by dimer dissociation and metal loss, but the mechanisms by which the metal-free monomer aggregates remain incompletely understood. Here we use implicit solvent all-atom Monte Carlo (MC) methods to investigate the local unfolding dynamics of the β-barrel-forming SOD1 monomer. Although event-to-event variations are large, on average, we find clear differences in dynamics among the eight strands forming the β-barrel. Most dynamic is the eighth strand, β8, which is located in the dimer... (More)
Copper, zinc superoxide dismutase 1 (SOD1) is a ubiquitous homodimeric enzyme, whose misfolding and aggregation play a potentially key role in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). SOD1 aggregation is thought to be preceded by dimer dissociation and metal loss, but the mechanisms by which the metal-free monomer aggregates remain incompletely understood. Here we use implicit solvent all-atom Monte Carlo (MC) methods to investigate the local unfolding dynamics of the β-barrel-forming SOD1 monomer. Although event-to-event variations are large, on average, we find clear differences in dynamics among the eight strands forming the β-barrel. Most dynamic is the eighth strand, β8, which is located in the dimer interface of native SOD1. For the four strands in or near the dimer interface (β1, β2, β7, and β8), we perform aggregation simulations to assess the propensity of these chain segments to self-associate. We find that β1 and β2 readily self-associate to form intermolecular parallel β-sheets, whereas β8 shows a very low aggregation propensity. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
The Journal of Physical Chemistry Part B
volume
117
issue
31
pages
9194 - 9202
publisher
The American Chemical Society
external identifiers
  • wos:000323082200007
  • pmid:23844996
  • scopus:84881421762
ISSN
1520-5207
DOI
10.1021/jp404500b
language
English
LU publication?
yes
id
b7503999-f52b-46e5-93e9-5f13b543d5b3 (old id 3955962)
date added to LUP
2013-08-02 13:22:42
date last changed
2019-04-10 01:05:15
@article{b7503999-f52b-46e5-93e9-5f13b543d5b3,
  abstract     = {Copper, zinc superoxide dismutase 1 (SOD1) is a ubiquitous homodimeric enzyme, whose misfolding and aggregation play a potentially key role in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). SOD1 aggregation is thought to be preceded by dimer dissociation and metal loss, but the mechanisms by which the metal-free monomer aggregates remain incompletely understood. Here we use implicit solvent all-atom Monte Carlo (MC) methods to investigate the local unfolding dynamics of the β-barrel-forming SOD1 monomer. Although event-to-event variations are large, on average, we find clear differences in dynamics among the eight strands forming the β-barrel. Most dynamic is the eighth strand, β8, which is located in the dimer interface of native SOD1. For the four strands in or near the dimer interface (β1, β2, β7, and β8), we perform aggregation simulations to assess the propensity of these chain segments to self-associate. We find that β1 and β2 readily self-associate to form intermolecular parallel β-sheets, whereas β8 shows a very low aggregation propensity.},
  author       = {Bille, Anna and Jonsson, Sigurdur and Akke, Mikael and Irbäck, Anders},
  issn         = {1520-5207},
  language     = {eng},
  number       = {31},
  pages        = {9194--9202},
  publisher    = {The American Chemical Society},
  series       = {The Journal of Physical Chemistry Part B},
  title        = {Local Unfolding and Aggregation Mechanisms of SOD1: A Monte Carlo Exploration.},
  url          = {http://dx.doi.org/10.1021/jp404500b},
  volume       = {117},
  year         = {2013},
}