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Ensemble-based multiscale modelling of DNA base pair tautomerism in the absence and presence of external electric fields

Gheorghiu, Alexander; (2021) Ensemble-based multiscale modelling of DNA base pair tautomerism in the absence and presence of external electric fields. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Löwdin proposed that the base pair double proton transfer (DPT) tautomers, A*T* and G*C*, may cause mutations during the replication process via mismatches, e.g. the pairing of A* with C, and G* with T. This thesis uses multiscale modelling techniques to study base pair tautomerism in a realistic DNA system. Previous studies typically consist of idealised gas-phase quantum models which often produce conflicting results. The aims of this thesis are to i) reassess the viability of base pair tautomerism as a contributory mechanism towards spontaneous single point mutations in DNA and ii) predict how external electric fields (ranging from strengths of 10⁴ V/m to 10⁹ V/m) influence the thermodynamic stability of the tautomers and the kinetics of the DPT reaction. An ensemble of reaction coordinates and the rate coefficients of tautomerism for each base pair in aqueous DNA is calculated using quantum mechanics/molecular mechanics (QM/MM) methods. Performing an ensemble of calculations accounts for the stochastic aspects of my simulations while allowing for easier identification of systematic errors. The results show that DPT between base pairs has a negligible contribution towards spontaneous mutations in DNA. This is because the tautomer has a maximum half-life in the picosecond range, which is significantly smaller than the milliseconds it takes for DNA to unwind during replication, and statistically, they revert towards their canonical forms via a mostly barrierless process. The application of larger electric fields (10⁹ V/m) parallel to base pair hydrogen bonds is found to increase the lifetime of the tautomers by one order of magnitude at most. In the context of mutations in human beings, the effect of external electric fields on base pair tautomerism is deemed insignificant. The ensemble-based methodology utilised in this study has shown that several different proton transfer reaction pathways, each with varying probabilities, occur within the same base pair. This contribution has provided new insight towards the multiscale modelling of biochemical processes, specifically those involving multiple reaction pathways, such as occur in enzyme catalysis.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Ensemble-based multiscale modelling of DNA base pair tautomerism in the absence and presence of external electric fields
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/10126032
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