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Title: Dynamics of protein aggregation and oligomer formation governed by secondary nucleation

Abstract

The formation of aggregates in many protein systems can be significantly accelerated by secondary nucleation, a process where existing assemblies catalyse the nucleation of new species. In particular, secondary nucleation has emerged as a central process controlling the proliferation of many filamentous protein structures, including molecular species related to diseases such as sickle cell anemia and a range of neurodegenerative conditions. Increasing evidence suggests that the physical size of protein filaments plays a key role in determining their potential for deleterious interactions with living cells, with smaller aggregates of misfolded proteins, oligomers, being particularly toxic. It is thus crucial to progress towards an understanding of the factors that control the sizes of protein aggregates. However, the influence of secondary nucleation on the time evolution of aggregate size distributions has been challenging to quantify. This difficulty originates in large part from the fact that secondary nucleation couples the dynamics of species distant in size space. Here, we approach this problem by presenting an analytical treatment of the master equation describing the growth kinetics of linear protein structures proliferating through secondary nucleation and provide closed-form expressions for the temporal evolution of the resulting aggregate size distribution. We show how the availability ofmore » analytical solutions for the full filament distribution allows us to identify the key physical parameters that control the sizes of growing protein filaments. Furthermore, we use these results to probe the dynamics of the populations of small oligomeric species as they are formed through secondary nucleation and discuss the implications of our work for understanding the factors that promote or curtail the production of these species with a potentially high deleterious biological activity.« less

Authors:
; ; ;  [1]
  1. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW (United Kingdom)
Publication Date:
OSTI Identifier:
22493494
Resource Type:
Journal Article
Journal Name:
Journal of Chemical Physics
Additional Journal Information:
Journal Volume: 143; Journal Issue: 5; Other Information: (c) 2015 AIP Publishing LLC; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0021-9606
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AGGLOMERATION; ANEMIAS; AVAILABILITY; FILAMENTS; NUCLEATION; POTENTIALS; PROBES; PROTEIN STRUCTURE; PROTEINS; TOXICITY

Citation Formats

Michaels, Thomas C. T.,, Lazell, Hamish W., Arosio, Paolo, and Knowles, Tuomas P. J.,. Dynamics of protein aggregation and oligomer formation governed by secondary nucleation. United States: N. p., 2015. Web. doi:10.1063/1.4927655.
Michaels, Thomas C. T.,, Lazell, Hamish W., Arosio, Paolo, & Knowles, Tuomas P. J.,. Dynamics of protein aggregation and oligomer formation governed by secondary nucleation. United States. https://doi.org/10.1063/1.4927655
Michaels, Thomas C. T.,, Lazell, Hamish W., Arosio, Paolo, and Knowles, Tuomas P. J.,. 2015. "Dynamics of protein aggregation and oligomer formation governed by secondary nucleation". United States. https://doi.org/10.1063/1.4927655.
@article{osti_22493494,
title = {Dynamics of protein aggregation and oligomer formation governed by secondary nucleation},
author = {Michaels, Thomas C. T., and Lazell, Hamish W. and Arosio, Paolo and Knowles, Tuomas P. J.,},
abstractNote = {The formation of aggregates in many protein systems can be significantly accelerated by secondary nucleation, a process where existing assemblies catalyse the nucleation of new species. In particular, secondary nucleation has emerged as a central process controlling the proliferation of many filamentous protein structures, including molecular species related to diseases such as sickle cell anemia and a range of neurodegenerative conditions. Increasing evidence suggests that the physical size of protein filaments plays a key role in determining their potential for deleterious interactions with living cells, with smaller aggregates of misfolded proteins, oligomers, being particularly toxic. It is thus crucial to progress towards an understanding of the factors that control the sizes of protein aggregates. However, the influence of secondary nucleation on the time evolution of aggregate size distributions has been challenging to quantify. This difficulty originates in large part from the fact that secondary nucleation couples the dynamics of species distant in size space. Here, we approach this problem by presenting an analytical treatment of the master equation describing the growth kinetics of linear protein structures proliferating through secondary nucleation and provide closed-form expressions for the temporal evolution of the resulting aggregate size distribution. We show how the availability of analytical solutions for the full filament distribution allows us to identify the key physical parameters that control the sizes of growing protein filaments. Furthermore, we use these results to probe the dynamics of the populations of small oligomeric species as they are formed through secondary nucleation and discuss the implications of our work for understanding the factors that promote or curtail the production of these species with a potentially high deleterious biological activity.},
doi = {10.1063/1.4927655},
url = {https://www.osti.gov/biblio/22493494}, journal = {Journal of Chemical Physics},
issn = {0021-9606},
number = 5,
volume = 143,
place = {United States},
year = {Fri Aug 07 00:00:00 EDT 2015},
month = {Fri Aug 07 00:00:00 EDT 2015}
}