Thesis
Theory and simulation of DNA damage and supercoiling
- Abstract:
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We employ an array of methods including statistical mechanics and computer simulation to better understand how both damaged and undamaged DNA respond to linear and torsional mechanical stress and the effect of damage on supercoiled phenomena.
Via the use of an all-atom thymine dimer residue, damaged linear and circular DNA were simulated atomistically for various biologically relevant systems using the AmberTools molecular dynamics package. Local structural parameters and global properties are characterised and shown to agree well with experimental data.
Using oxDNA, a nucleotide level coarse-grained model of DNA, we make use of another model for a thymine dimer to probe larger systems and for longer times, investigating a 336-bp minicircles and its negatively supercoiled topoisomers as well as a 160-bp minicircle. We show that the presence of a thymine dimer causes a sharp local increase in curvature as well as increase in negative writhe for the under-twisted systems - potentially helping to suppress bubble formation.
A planar model for damaged DNA via a piecewise construction of worm-like chains with different bending moduli is developed. This model is then applied to curls, plectonemes and minicircles. A more general twist-storing model of plectonemes is also developed and shown to reproduce phase diagrams in accordance with experiments and simulations.
The theory of thermal fluctuations through a polymeric path integral is developed for a ribbon-like model of DNA in the fixed linking number ensemble. This theory is then applied to several systems such as straight chains and solenoids, successfully reproducing some well-known results. Finally we apply the theory to a previously intractable system of non-trivial saddle points, with the general systematic methodology elucidated.
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- Files:
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(Preview, Dissemination version, pdf, 22.3MB, Terms of use)
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Authors
Contributors
- Institution:
- University of Oxford
- Division:
- MPLS
- Department:
- Physics
- Sub department:
- Condensed Matter Physics
- Role:
- Contributor
- ORCID:
- 0000-0002-8438-910X
- Institution:
- University of York
- Role:
- Contributor
- Institution:
- University of Oxford
- Division:
- MPLS
- Department:
- Chemistry
- Sub department:
- Physical & Theoretical Chem
- Oxford college:
- Queen's College
- Role:
- Supervisor
- ORCID:
- 0000-0002-2226-9524
- Funder identifier:
- https://ror.org/054225q67
- Funding agency for:
- Selby, M
- Grant:
- S_3772
- DOI:
- Type of award:
- DPhil
- Level of award:
- Doctoral
- Awarding institution:
- University of Oxford
- Language:
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English
- Keywords:
- Subjects:
- Deposit date:
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2024-02-14
- ARK identifier:
Terms of use
- Copyright holder:
- Selby, M
- Copyright date:
- 2023
- Licence:
- CC Attribution (CC BY)
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