Photophysics and photochemistry of “non-natural” DNA building blocks

Background:
Over the last decade, a number of alternative nucleobase units have been demonstrated that have allowed an expansion of the genetic alphabet.[1-2] These unnatural base pairs have even been introduced into living bacteria.[3]. Currently, there are a huge number of scientific questions surrounding the fundamental properties of “non-natural” nucleobases. One such question relates to the photostability of non-natural nucleobases. While the native nucleobases are well known for their intrinsic photostability and their ability to convert harmful UV radiation into benign heat energy, the behaviour of non-native nucleobases in the presence of UV radiation is much more poorly understood.[3] Indeed the photophysics of these non-natural nucleobases has been very poorly studied to date. This project will aim to contribute to this area by measuring the electronic spectra of a series of non-natural nucleobases as an isolated, gas-phase species to understand their intrinsic ability to absorb light, as a function of charge state. The photofragmentation pathways of the nucleobase will be mapped as a function of excitation wavelength to provide preliminary information on the photophysics. These measurements will allow us to assess how photostable the non-native nucleobase is compared to native nucleobases. There will also be opportunities to perform ab initio calculations to support the experimental work.

Objectives:
The key objectives for the project will be: 1. To map out the electronic excited states of a series of non-natural nucleobases, e.g. NaM and 5SICS, using Resonance Enhanced Multiphoton Ionisation (REMPI) spectroscopy. 2. To compare the results of the REMPI measurements to excited state spectra obtained using laser photodissociation spectroscopy of electrosprayed nucleobases via laser-interfaced mass spectrometry. This section of the project will allow the systems to be studied as nucleosides and nucleotides. 3. Implement time-resolved pump-probe spectroscopy to directly measure whether excited state decay in these systems occur on an ultrafast timescale.

Experimental Approach and Novelty:
REMPI spectroscopy will be conducted in a custom-built molecular-beam spectrometer (MCRC group), while laser photodissociation measurements will be conducted in a laser-interfaced mass spectrometer (CED) which includes an electrospray ionisation (ESI) source that can be used to transfer a wide range of molecular ions directly into the gas-phase.[4,5] To date, fundamental studies of the photophysics and photochemistry of non-natural nucleobases are rare, so the proposed work will be novel with potential high-impact. In the second stage of the project, the student will have the opportunity to work with the laser experimental officer to implement time-resolved measurements, to directly probe the photophysics of the excited states. Again, these measurements would be internationally unique, providing a highly novel project. As part of the project, there may be an opportunity to perform experiments on the Central Laser Facility’s ULTRA system to perform corresponding measurements on solution-phase species.

Training: Full training in laser spectroscopy (use of class 4 laser systems) and mass spectrometry (soft ionization techniques and HPLC) will be provided, along with training in data analysis and storage. Training will also be provided in computational chemistry, covering ab initio and density functional theory methods. The Dessent/Cockett research groups foster a lively scientific environment for students, with regular group meetings, directed literature reading, close links to the other internal and external research groups, rapid publication of post-graduate results and attendance at external UK and international scientific meetings.

All Chemistry research students have access to our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills: https://www.york.ac.uk/chemistry/postgraduate/idtc/

The Department of Chemistry holds an Athena SWAN Gold Award and is committed to supporting equality and diversity for all staff and students. The Department strives to provide a working environment which allows all staff and students to contribute fully, to flourish, and to excel: https://www.york.ac.uk/chemistry/ed/. This PhD project is available to study full-time or part-time (50%).

This PhD will formally start on 1 October 2020. Induction activities will start on 28 September.