Moment dynamics of oligomer formation in protein amyloid aggregation with secondary nucleation

The abnormal aggregation of proteins into amyloid fibrils, usually implemented by a series of biochemical reactions, is associated with various neurodegenerative disorders. Considering the intrinsic stochasticity in the involving biochemical reactions, a general chemical master equation model for de...

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Bibliographic Details
Published in:Advances in continuous and discrete models 2024-08, Vol.2024 (1), p.25, Article 25
Main Authors: Ding, Yamin, Cai, Liming, Kang, Yanmei
Format: Article
Language:English
Subjects:
Aggregates
Algorithms
Analysis
Biomathematical Modelling and Stochastic Analysis
Chemical reactions
Difference and Functional Equations
Functional Analysis
Mathematics
Mathematics and Statistics
Monomers
Nucleation
Oligomers
Ordinary Differential Equations
Partial Differential Equations
Peptides
Polymerization
Proteins
Sensitivity analysis
Time dependence
Toxicity
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Summary:The abnormal aggregation of proteins into amyloid fibrils, usually implemented by a series of biochemical reactions, is associated with various neurodegenerative disorders. Considering the intrinsic stochasticity in the involving biochemical reactions, a general chemical master equation model for describing the process from oligomer production to fibril formation is established, and then the lower-order statistical moments of different molecule species are captured by the derivative matching closed system, and the long-time accuracy is verified using the Gillespie algorithm. It is revealed that the aggregation of monomers into oligomers is highly dependent on the initial number of misfolded monomers; the formation of oligomers can be effectively inhibited by reducing the misfolding rate, the primary nucleation rate, elongation rate, and secondary nucleation rate; as the conversion rate decreases, the number of oligomers increases over a long time scale. In particular, sensitivity analysis shows that the quantities of oligomers are more sensitive to monomer production and protein misfolding; the secondary nucleation is more important than the primary nucleation in oligomer formation. These findings are helpful for understanding and predicting the dynamic mechanism of amyloid aggregation from the viewpoint of quantitative analysis.
ISSN:2731-4235
1687-1839
2731-4235
1687-1847
DOI:10.1186/s13662-024-03819-2