Advanced

Monte Carlo simulations of protein amyloid formation reveal origin of sigmoidal aggregation kinetics.

Linse, Björn and Linse, Sara LU (2011) In Molecular BioSystems 7. p.2296-2303
Abstract
Severe conditions and lack of cure for many amyloid diseases make it highly desired to understand the underlying principles of formation of fibrillar aggregates (amyloid). Here, amyloid formation from peptides was studied using Monte Carlo simulations. Systems of 20, 50, 100, 200 or 500 hexapeptides were simulated. Association kinetics were modeled equal for fibrillar and other (inter- and intra-peptide) contacts and assumed to be faster the lower the effective contact order, which represents the distance in space. Attempts to form contacts were thus accepted with higher probability the lower the effective contact order, whereby formation of new contacts next to preexisting ones is favored by shorter physical separation. Kinetic... (More)
Severe conditions and lack of cure for many amyloid diseases make it highly desired to understand the underlying principles of formation of fibrillar aggregates (amyloid). Here, amyloid formation from peptides was studied using Monte Carlo simulations. Systems of 20, 50, 100, 200 or 500 hexapeptides were simulated. Association kinetics were modeled equal for fibrillar and other (inter- and intra-peptide) contacts and assumed to be faster the lower the effective contact order, which represents the distance in space. Attempts to form contacts were thus accepted with higher probability the lower the effective contact order, whereby formation of new contacts next to preexisting ones is favored by shorter physical separation. Kinetic discrimination was invoked by using two different life-times for formed contacts. Contacts within amyloid fibrils were assumed to have on average longer life-time than other contacts. We find that the model produces fibrillation kinetics with a distinct lag phase, and that the fibrillar contacts need to dissociate on average 5-20 times slower than all other contacts for the fibrillar structure to dominate at equilibrium. Analysis of the species distribution along the aggregation process shows that no other intermediate is ever more populated than the dimer. Instead of a single nucleation event there is a concomitant increase in average aggregate size over the whole system, and the occurrence of multiple parallel processes makes the process more reproducible the larger the simulated system. The sigmoidal shape of the aggregation curves arises from cooperativity among multiple interactions within each pair of peptides in a fibril. A governing factor is the increasing probability as the aggregation process proceeds of neighboring reinforcing contacts. The results explain the very strong bias towards cross β-sheet fibrils in which the possibilities for cooperativity among interactions involving neighboring residues and the repetitive use of optimal side-chain interactions are explored at maximum. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular BioSystems
volume
7
pages
2296 - 2303
publisher
Royal Society of Chemistry
external identifiers
  • wos:000291559900022
  • pmid:21589952
  • scopus:79959243317
ISSN
1742-2051
DOI
10.1039/c0mb00321b
language
English
LU publication?
yes
id
75d68bed-766e-4800-80da-690d1d866394 (old id 1972398)
date added to LUP
2011-06-17 12:45:20
date last changed
2017-07-09 03:49:46
@article{75d68bed-766e-4800-80da-690d1d866394,
  abstract     = {Severe conditions and lack of cure for many amyloid diseases make it highly desired to understand the underlying principles of formation of fibrillar aggregates (amyloid). Here, amyloid formation from peptides was studied using Monte Carlo simulations. Systems of 20, 50, 100, 200 or 500 hexapeptides were simulated. Association kinetics were modeled equal for fibrillar and other (inter- and intra-peptide) contacts and assumed to be faster the lower the effective contact order, which represents the distance in space. Attempts to form contacts were thus accepted with higher probability the lower the effective contact order, whereby formation of new contacts next to preexisting ones is favored by shorter physical separation. Kinetic discrimination was invoked by using two different life-times for formed contacts. Contacts within amyloid fibrils were assumed to have on average longer life-time than other contacts. We find that the model produces fibrillation kinetics with a distinct lag phase, and that the fibrillar contacts need to dissociate on average 5-20 times slower than all other contacts for the fibrillar structure to dominate at equilibrium. Analysis of the species distribution along the aggregation process shows that no other intermediate is ever more populated than the dimer. Instead of a single nucleation event there is a concomitant increase in average aggregate size over the whole system, and the occurrence of multiple parallel processes makes the process more reproducible the larger the simulated system. The sigmoidal shape of the aggregation curves arises from cooperativity among multiple interactions within each pair of peptides in a fibril. A governing factor is the increasing probability as the aggregation process proceeds of neighboring reinforcing contacts. The results explain the very strong bias towards cross β-sheet fibrils in which the possibilities for cooperativity among interactions involving neighboring residues and the repetitive use of optimal side-chain interactions are explored at maximum.},
  author       = {Linse, Björn and Linse, Sara},
  issn         = {1742-2051},
  language     = {eng},
  pages        = {2296--2303},
  publisher    = {Royal Society of Chemistry},
  series       = {Molecular BioSystems},
  title        = {Monte Carlo simulations of protein amyloid formation reveal origin of sigmoidal aggregation kinetics.},
  url          = {http://dx.doi.org/10.1039/c0mb00321b},
  volume       = {7},
  year         = {2011},
}