---
_id: '10357'
abstract:
- lang: eng
text: The misfolding and aggregation of proteins into linear fibrils is widespread
in human biology, for example, in connection with amyloid formation and the pathology
of neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. The
oligomeric species that are formed in the early stages of protein aggregation
are of great interest, having been linked with the cellular toxicity associated
with these conditions. However, these species are not characterized in any detail
experimentally, and their properties are not well understood. Many of these species
have been found to have approximately spherical morphology and to be held together
by hydrophobic interactions. We present here an analytical statistical mechanical
model of globular oligomer formation from simple idealized amphiphilic protein
monomers and show that this correlates well with Monte Carlo simulations of oligomer
formation. We identify the controlling parameters of the model, which are closely
related to simple quantities that may be fitted directly from experiment. We predict
that globular oligomers are unlikely to form at equilibrium in many polypeptide
systems but instead form transiently in the early stages of amyloid formation.
We contrast the globular model of oligomer formation to a well-established model
of linear oligomer formation, highlighting how the differing ensemble properties
of linear and globular oligomers offer a potential strategy for characterizing
oligomers from experimental measurements.
acknowledgement: We acknowledge support from the Schiff Foundation (A.J.D.), the Royal
Society (A.Š.), the Academy of Medical Sciences and Wellcome Trust (A.Š.), Peterhouse,
Cambridge (T.C.T.M.), the Swiss National Science foundation (T.C.T.M.), the Wellcome
Trust (T.P.J.K.), the Cambridge Centre for Misfolding Diseases (T.P.J.K.), the BBSRC
(T.P.J.K.), the Frances and Augustus Newman foundation (T.P.J.K.). The research
leading to these results has received funding from the European Research Council
under the European Union’s Seventh Framework Programme (Grant FP7/2007-2013) through
the ERC Grant PhysProt (Agreement No. 337969). We thank Daan Frenkel for several
useful discussions.
article_processing_charge: No
article_type: original
author:
- first_name: Alexander J.
full_name: Dear, Alexander J.
last_name: Dear
- first_name: Anđela
full_name: Šarić, Anđela
id: bf63d406-f056-11eb-b41d-f263a6566d8b
last_name: Šarić
orcid: 0000-0002-7854-2139
- first_name: Thomas C. T.
full_name: Michaels, Thomas C. T.
last_name: Michaels
- first_name: Christopher M.
full_name: Dobson, Christopher M.
last_name: Dobson
- first_name: Tuomas P. J.
full_name: Knowles, Tuomas P. J.
last_name: Knowles
citation:
ama: Dear AJ, Šarić A, Michaels TCT, Dobson CM, Knowles TPJ. Statistical mechanics
of globular oligomer formation by protein molecules. The Journal of Physical
Chemistry B. 2018;122(49):11721-11730. doi:10.1021/acs.jpcb.8b07805
apa: Dear, A. J., Šarić, A., Michaels, T. C. T., Dobson, C. M., & Knowles, T.
P. J. (2018). Statistical mechanics of globular oligomer formation by protein
molecules. The Journal of Physical Chemistry B. American Chemical Society.
https://doi.org/10.1021/acs.jpcb.8b07805
chicago: Dear, Alexander J., Anđela Šarić, Thomas C. T. Michaels, Christopher M.
Dobson, and Tuomas P. J. Knowles. “Statistical Mechanics of Globular Oligomer
Formation by Protein Molecules.” The Journal of Physical Chemistry B. American
Chemical Society, 2018. https://doi.org/10.1021/acs.jpcb.8b07805.
ieee: A. J. Dear, A. Šarić, T. C. T. Michaels, C. M. Dobson, and T. P. J. Knowles,
“Statistical mechanics of globular oligomer formation by protein molecules,” The
Journal of Physical Chemistry B, vol. 122, no. 49. American Chemical Society,
pp. 11721–11730, 2018.
ista: Dear AJ, Šarić A, Michaels TCT, Dobson CM, Knowles TPJ. 2018. Statistical
mechanics of globular oligomer formation by protein molecules. The Journal of
Physical Chemistry B. 122(49), 11721–11730.
mla: Dear, Alexander J., et al. “Statistical Mechanics of Globular Oligomer Formation
by Protein Molecules.” The Journal of Physical Chemistry B, vol. 122, no.
49, American Chemical Society, 2018, pp. 11721–30, doi:10.1021/acs.jpcb.8b07805.
short: A.J. Dear, A. Šarić, T.C.T. Michaels, C.M. Dobson, T.P.J. Knowles, The Journal
of Physical Chemistry B 122 (2018) 11721–11730.
date_created: 2021-11-26T11:55:12Z
date_published: 2018-10-18T00:00:00Z
date_updated: 2021-11-26T12:40:02Z
day: '18'
doi: 10.1021/acs.jpcb.8b07805
extern: '1'
external_id:
pmid:
- '30336667'
intvolume: ' 122'
issue: '49'
keyword:
- materials chemistry
language:
- iso: eng
month: '10'
oa_version: None
page: 11721-11730
pmid: 1
publication: The Journal of Physical Chemistry B
publication_identifier:
eissn:
- 1520-5207
issn:
- 1520-6106
publication_status: published
publisher: American Chemical Society
quality_controlled: '1'
scopus_import: '1'
status: public
title: Statistical mechanics of globular oligomer formation by protein molecules
type: journal_article
user_id: 8b945eb4-e2f2-11eb-945a-df72226e66a9
volume: 122
year: '2018'
...