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Stochastic reaction-diffusion kinetics in the microscopic limit
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology. (ehrenberg)
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
2010 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 107, no 46, 19820-19825 p.Article in journal (Refereed) Published
Abstract [en]

Quantitative analysis of biochemical networks often requires consideration of both spatial and stochastic aspects of chemical processes. Despite significant progress in the field, it is still computationally prohibitive to simulate systems involving many reactants or complex geometries using a microscopic framework that includes the finest length and time scales of diffusion-limited molecular interactions. For this reason, spatially or temporally discretized simulations schemes are commonly used when modeling intracellular reaction networks. The challenge in defining such coarse-grained models is to calculate the correct probabilities of reaction given the microscopic parameters and the uncertainty in the molecular positions introduced by the spatial or temporal discretization. In this paper we have solved this problem for the spatially discretized Reaction-Diffusion Master Equation; this enables a seamless and physically consistent transition from the microscopic to the macroscopic frameworks of reaction-diffusion kinetics. We exemplify the use of the methods by showing that a phosphorylation-dephosphorylation motif, commonly observed in eukaryotic signaling pathways, is predicted to display fluctuations that depend on the geometry of the system.

 

 

Place, publisher, year, edition, pages
2010. Vol. 107, no 46, 19820-19825 p.
Keyword [en]
diffusion-limited, mesoscopic, master equation, Smoluchowski, spatial
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:uu:diva-133220DOI: 10.1073/pnas.1006565107ISI: 000284261800042PubMedID: 21041672OAI: oai:DiVA.org:uu-133220DiVA: diva2:360450
Available from: 2010-11-03 Created: 2010-11-03 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Modelling Approaches to Molecular Systems Biology
Open this publication in new window or tab >>Modelling Approaches to Molecular Systems Biology
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Systembiologisk modellering på molekylär nivå
Abstract [en]

Implementation and analysis of mathematical models can serve as a powerful tool in understanding how intracellular processes in bacteria affect the bacterial phenotype. In this thesis I have implemented and analysed models of a number of different parts of the bacterium E. coli in order to understand these types of connections. I have also developed new tools for analysis of stochastic reaction-diffusion models.

Resistance mutations in the E. coli ribosomes make the bacteria less susceptible to treatment with the antibiotic drug erythromycin compared to bacteria carrying wildtype ribosomes. The effect is dependent on efficient drug efflux pumps. In the absence of pumps for erythromycin, there is no difference in growth between wildtype and drug target resistant bacteria. I present a model explaining this unexpected phenotype, and also give the conditions for its occurrence.

Stochastic fluctuations in gene expression in bacteria, such as E. coli, result in stochastic fluctuations in biosynthesis pathways. I have characterised the effect of stochastic fluctuations in the parallel biosynthesis pathways of amino acids. I show how the average protein synthesis rate decreases with an increasing number of fluctuating amino acid production pathways. I further show how the cell can remedy this problem by using sensitive feedback control of transcription, and by optimising its expression levels of amino acid biosynthetic enzymes.

The pole-to-pole oscillations of the Min-proteins in E. coli are required for accurate mid-cell division. The phenotype of the Min-oscillations is altered in three different mutants: filamentous cells, round cells and cells with changed membrane lipid composition. I have shown that the wildtype and mutant phenotypes can be explained using a stochastic reaction-diffusion model.

In E. coli, the transcription elongation rate on the ribosmal RNA operon increases with increasing transcription initiation rate. In addition, the polymerase density varies along the ribosomal RNA operons. I present a DNA sequence dependent model that explains the transcription elongation rate speed-up, and also the density variation along the ribosomal operons. Both phenomena are explained by the RNA polymerase backtracking on the DNA.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 57 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 785
Keyword
stochastic reaction-diffuion kinetics, antibiotic drugs, efflux pumps, amino acid biosynthesis, Min-system, rRNA operon, transcription
National Category
Biochemistry and Molecular Biology
Research subject
Biology with specialization in Molecular Biotechnology
Identifiers
urn:nbn:se:uu:diva-132864 (URN)978-91-554-7941-1 (ISBN)
Public defence
2010-12-16, B21, BMC, Husargatan 3, Uppsala, 13:00 (English)
Opponent
Supervisors
Note
Felaktigt tryckt som Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 715Available from: 2010-11-24 Created: 2010-10-27 Last updated: 2011-03-21Bibliographically approved

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Elf, Johan

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