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Physical determinants of the self-replication of protein fibrils

Šaric, Andela; Buell, Alexander K.; Meisl, Georg; Michaels, Thomas C T; Dobson, Christopher M.; Linse, Sara LU ; Knowles, Tuomas P J and Frenkel, Daan (2016) In Nature Physics 12(9). p.874-880
Abstract

The ability of biological molecules to replicate themselves is the foundation of life, requiring a complex cellular machinery. However, a range of aberrant processes involve the self-replication of pathological protein structures without any additional assistance. One example is the autocatalytic generation of pathological protein aggregates, including amyloid fibrils, involved in neurodegenerative disorders. Here, we use computer simulations to identify the necessary requirements for the self-replication of fibrillar assemblies of proteins. We establish that a key physical determinant for this process is the affinity of proteins for the surfaces of fibrils. We find that self-replication can take place only in a very narrow regime of... (More)

The ability of biological molecules to replicate themselves is the foundation of life, requiring a complex cellular machinery. However, a range of aberrant processes involve the self-replication of pathological protein structures without any additional assistance. One example is the autocatalytic generation of pathological protein aggregates, including amyloid fibrils, involved in neurodegenerative disorders. Here, we use computer simulations to identify the necessary requirements for the self-replication of fibrillar assemblies of proteins. We establish that a key physical determinant for this process is the affinity of proteins for the surfaces of fibrils. We find that self-replication can take place only in a very narrow regime of inter-protein interactions, implying a high level of sensitivity to system parameters and experimental conditions. We then compare our theoretical predictions with kinetic and biosensor measurements of fibrils formed from the Aβ peptide associated with Alzheimer's disease. Our results show a quantitative connection between the kinetics of self-replication and the surface coverage of fibrils by monomeric proteins. These findings reveal the fundamental physical requirements for the formation of supra-molecular structures able to replicate themselves, and shed light on mechanisms in play in the proliferation of protein aggregates in nature.

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organization
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publication status
published
subject
in
Nature Physics
volume
12
issue
9
pages
7 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:84978763072
  • wos:000383219800016
ISSN
1745-2473
DOI
10.1038/nphys3828
language
English
LU publication?
yes
id
2e73a622-474b-484b-8e38-34d108630cbb
date added to LUP
2016-11-09 12:12:40
date last changed
2017-10-08 04:54:27
@article{2e73a622-474b-484b-8e38-34d108630cbb,
  abstract     = {<p>The ability of biological molecules to replicate themselves is the foundation of life, requiring a complex cellular machinery. However, a range of aberrant processes involve the self-replication of pathological protein structures without any additional assistance. One example is the autocatalytic generation of pathological protein aggregates, including amyloid fibrils, involved in neurodegenerative disorders. Here, we use computer simulations to identify the necessary requirements for the self-replication of fibrillar assemblies of proteins. We establish that a key physical determinant for this process is the affinity of proteins for the surfaces of fibrils. We find that self-replication can take place only in a very narrow regime of inter-protein interactions, implying a high level of sensitivity to system parameters and experimental conditions. We then compare our theoretical predictions with kinetic and biosensor measurements of fibrils formed from the Aβ peptide associated with Alzheimer's disease. Our results show a quantitative connection between the kinetics of self-replication and the surface coverage of fibrils by monomeric proteins. These findings reveal the fundamental physical requirements for the formation of supra-molecular structures able to replicate themselves, and shed light on mechanisms in play in the proliferation of protein aggregates in nature.</p>},
  author       = {Šaric, Andela and Buell, Alexander K. and Meisl, Georg and Michaels, Thomas C T and Dobson, Christopher M. and Linse, Sara and Knowles, Tuomas P J and Frenkel, Daan},
  issn         = {1745-2473},
  language     = {eng},
  month        = {09},
  number       = {9},
  pages        = {874--880},
  publisher    = {Nature Publishing Group},
  series       = {Nature Physics},
  title        = {Physical determinants of the self-replication of protein fibrils},
  url          = {http://dx.doi.org/10.1038/nphys3828},
  volume       = {12},
  year         = {2016},
}