Kinetics of seeded protein aggregation : Theory and application
(2025) In Journal of Chemical Physics 163(4).- Abstract
“Seeding” is the addition of preformed fibrils to a solution of monomeric protein to accelerate its aggregation into new fibrils. It is a versatile and widely used tool for scientists studying protein aggregation kinetics, as it enables the isolation and separate study of discrete reaction steps contributing to protein aggregation, specifically elongation and secondary nucleation. However, the seeding levels required to achieve dominating effects on each of these steps separately have been established largely by trial-and-error due in part to the lack of availability of integrated rate laws valid for moderate to high seeding levels and generally applicable to all common underlying reaction mechanisms. Here, we improve on a recently... (More)
“Seeding” is the addition of preformed fibrils to a solution of monomeric protein to accelerate its aggregation into new fibrils. It is a versatile and widely used tool for scientists studying protein aggregation kinetics, as it enables the isolation and separate study of discrete reaction steps contributing to protein aggregation, specifically elongation and secondary nucleation. However, the seeding levels required to achieve dominating effects on each of these steps separately have been established largely by trial-and-error due in part to the lack of availability of integrated rate laws valid for moderate to high seeding levels and generally applicable to all common underlying reaction mechanisms. Here, we improve on a recently developed mathematical method based on Lie symmetries for solving differential equations and with it derive such an integrated rate law. We subsequently develop simple expressions for the amounts of seed required to isolate each step. We rationalize the empirical observation that fibril seeds must often be broken up into small pieces to successfully isolate elongation. We also derive expressions for average fibril lengths at different times in the aggregation reaction and explore different methods to break up fibrils. This paper will provide an invaluable reference for future experimental and theoretical studies in which seeding techniques are employed and should enable more sophisticated analyses than have been performed to date.
(Less)
- author
- Dear, Alexander J. LU ; Meisl, Georg ; Hu, Jing LU ; Knowles, Tuomas P.J. and Linse, Sara LU
- organization
- publishing date
- 2025-07-28
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Chemical Physics
- volume
- 163
- issue
- 4
- article number
- 045101
- publisher
- American Institute of Physics (AIP)
- external identifiers
-
- scopus:105012039569
- pmid:40728257
- ISSN
- 0021-9606
- DOI
- 10.1063/5.0273677
- language
- English
- LU publication?
- yes
- additional info
- Publisher Copyright: © 2025 Author(s).
- id
- b5c0c1c1-13af-44df-95ec-17c24a3b431e
- date added to LUP
- 2025-12-12 14:21:05
- date last changed
- 2025-12-12 14:21:27
@article{b5c0c1c1-13af-44df-95ec-17c24a3b431e,
abstract = {{<p>“Seeding” is the addition of preformed fibrils to a solution of monomeric protein to accelerate its aggregation into new fibrils. It is a versatile and widely used tool for scientists studying protein aggregation kinetics, as it enables the isolation and separate study of discrete reaction steps contributing to protein aggregation, specifically elongation and secondary nucleation. However, the seeding levels required to achieve dominating effects on each of these steps separately have been established largely by trial-and-error due in part to the lack of availability of integrated rate laws valid for moderate to high seeding levels and generally applicable to all common underlying reaction mechanisms. Here, we improve on a recently developed mathematical method based on Lie symmetries for solving differential equations and with it derive such an integrated rate law. We subsequently develop simple expressions for the amounts of seed required to isolate each step. We rationalize the empirical observation that fibril seeds must often be broken up into small pieces to successfully isolate elongation. We also derive expressions for average fibril lengths at different times in the aggregation reaction and explore different methods to break up fibrils. This paper will provide an invaluable reference for future experimental and theoretical studies in which seeding techniques are employed and should enable more sophisticated analyses than have been performed to date.</p>}},
author = {{Dear, Alexander J. and Meisl, Georg and Hu, Jing and Knowles, Tuomas P.J. and Linse, Sara}},
issn = {{0021-9606}},
language = {{eng}},
month = {{07}},
number = {{4}},
publisher = {{American Institute of Physics (AIP)}},
series = {{Journal of Chemical Physics}},
title = {{Kinetics of seeded protein aggregation : Theory and application}},
url = {{http://dx.doi.org/10.1063/5.0273677}},
doi = {{10.1063/5.0273677}},
volume = {{163}},
year = {{2025}},
}