Electron attachment to biomolecular clusters: probing the role of multiple scattering in radio-sensitivity.

The aim of this fellowship is to advance our understanding of how the chemical environment affects electron attachment to biomolecules. Electron attachment processes play an important role in radiation damage to biological material. In particular, electrons released by the ionization of local molecules (mainly water) can lose energy in a series of collisions before attaching to nucleobases in DNA. The resultant negative ions may be unstable and hence fragment yielding reactive species. A high density of such dissociation events in DNA constitutes a clustered lesion, recognised as a key precursor to mutations and cancers. Detailed knowledge of how electrons attach to biomolecules and the stabilities of the resultant anionic states is therefore essential to understand radiation damage on the molecular scale. Moreover characterising low-energy electron interactions with specific biomolecules can inform how manipulating their chemical environment with dopants can affect their radio-sensitivity with important applications in radiotherapy and radiation protection.The project will be centred on the development of an original experimental system to irradiate hydrogen-bonded biomolecular clusters with electrons at precisely defined energies (around 1meV to 15eV) and analyse the resultant anions by mass spectrometry. The key strength, novelty, and challenge will lie in applying the deflection of polar species in inhomogeneous electric fields (Stark deflection) to provide exceptional control over the target cluster configurations before the interactions with electrons. To date, direct comparisons with theory have been limited by the spread of neutral cluster sizes in experiments. The programme will be carried out in close collaboration with leading theoreticians (Gorfinkiel, OU, and Fabrikant, University of Nebraska) pioneering new methods to simulate electron scattering from / attachment to molecules within clusters. Electron interactions with specific neutral clusters will therefore be probed in equivalent experiments and calculations for the first time. The initial biomolecular targets will be complexes comprising water molecules, DNA bases, and a related azabenzene molecule, pyridine. Understanding the molecular-scale processes that initiate radiation damage in biological material has recently motivated extensive research into low-energy electron interactions with biomolecules. Experimental and theoretical studies of gas-phase biomolecules have revealed detailed information about the electron attachment sites and fragmentation patterns of specific anions. However hydrogen bonding can dramatically change the electron affinities of molecules as well as introducing new pathways for energy dissipation and electron loss from anionic states. The interpretation of experiments on biomolecular clusters without size selection and on condensed biomolecules is compromised by the lack of precise knowledge of the target and by dielectric surface charging, respectively. Size-selected neutral clusters provide a powerful test case to probe the effects of hydrogen bonding, notably by studying fragment anion production from a key biomolecule as a function of the precise number of associated water molecules. In summary, my objective is to develop a unique programme of experiments with strong theoretical support to advance our understanding of electron attachment processes in size-selected neutral clusters as model multi-molecular systems. This research will help to bridge the complexity gap between understanding radiation-induced processes in isolated molecules and in condensed material, with applications in modelling and potentially modifying biological damage processes on the nanoscale.

The aim of my research is to advance our understanding of how the chemical environment affects electron attachment to biomolecules. This will have a major impact on the effort to trace radiation effects in biological tissue to critical nanoscale physical / chemical processes. Current innovations in drug delivery techniques, for example using doped fullerenes, offer the possibility of attaching specific molecules to DNA sites within targeted cells. This presents an exceptional opportunity for society: by understanding the mechanisms by which associated molecules enhance the radiosensitivity of key biomolecules, we can predict the effects of potential new radiosensitizer drugs. Research into radiation induced intermolecular processes therefore has a central role to play in improving the efficacy of radiotherapy treatments for cancers. The associated benefits in our ageing society in terms of quality of life and providing economically-viable healthcare are considerable.Low energy electrons are by far the most abundant species produced in irradiated tissue and can attach to nucleobases in DNA. The resultant negative ions may be unstable and hence yield reactive species. A high density of these events in DNA constitutes a clustered lesion, recognised as a key precursor to cell death, as well as mutations and cancers. Therefore, modifying the chemical environment to enhance or suppress low energy electron induced DNA base fragmentation has enormous radiosensitizing potential. To better understand these processes, my fellowship is centred on experiments probing electron interactions with small clusters of biomolecules. A novel Stark deflection application will provide exceptional control over the cluster configuration, thus clarifying data interpretations and strengthening comparisons with simulations. This approach will lead to new insights that can guide innovations in cancer therapies as well as assessments of the risks of low dose radiation exposure.The key to maximizing the benefits of the fellowship for society will rest on linking my work to research and development across the traditional boundaries between disciplines. I will work in partnership with a team (Garcia and co-workers) pioneering radiation damage models based on nanoscale data including low energy electron induced processes. The group collaborates with oncologists in order to refine predictions of radiotherapy effects in cancerous and healthy tissue. A further important interdisciplinary link is through the Nano-scale insights into ion beam cancer therapy EU COST network. This initiative coordinates measurements of molecular-scale interactions, Monte-Carlo modelling of tissue-scale effects, and radiobiological research with ion-beam therapy applications at world-leading accelerator facilities, notably GSI Darmstadt. My current teaching role on the Masters level course Radiotherapy and its Physics at the Open University has provided further opportunities to liaise with leading clinical scientists at centres including UCH, Addenbrookes Hospital, and The Institute of Cancer Research: Royal Cancer Hospital. This direct interface with cutting-edge radiotherapy innovation and provision will be invaluable for the dissemination of my results. Moreover these links will enable me to channel my experiments to understand electron attachments effects in the most promising radiation chemistries.In summary, my research will have applications in identifying new radiosensitizing agents and in the development of precise radiation damage models based on nanoscale interactions. The biomedical impact will be maximized through regular meetings and collaborations in an extensive interdisciplinary network. Thus my research will benefit society by contributing to innovations in radiotherapy, a key tool in the bid to control cancer.