Irradiation of biomolecular clusters: model systems for the study of radiation damage in living material

Lead Research Organisation: Open University
Department Name: Physical Sciences

Abstract

Abstract from the Case for Support document (section 2):This research project is centred upon the parallel construction, development, and use of two complimentary experimental systems to study processes induced by ionisation in irradiated biomolecular systems. The principle objective is to compare the effects of irradiating a specific target molecule within a cluster with the case of the molecule in isolation. In addition to their fundamental interest in molecular and statistical physics, these experiments will help to bridge the complexity gap between the current understanding of radiation effects in the gas phase and in an absorbing biological medium. This represents a major current research challenge for physicists, chemists, and biologists, with important applications in quantifying the effects of exposure to different types of radiation during cancer therapies.The first experimental system is a versatile and mobile source for hydrated DNA base clusters, proposed for construction at the Open University. During the three year programme, this source will be used to carry out 2- and 1-photon electronic excitation experiments to probe the effects of solvated water molecules upon the valence and Rydberg energy states of key biomolecules and the associated dissociation pathways. The second experimental system, located at the Nuclear Physics Institute of Lyon, will enable a detailed study to be carried out on collisions between fast protons and mass-selected cluster ions comprising DNA bases and water molecules. The major technical challenge in this part of the project is the development of a multi-coincidence detection system for the characterisation of ionisation showers, electron emission, and free radical production induced by proton-cluster collisions. These inter-molecular processes are believed to play important roles in radiation damage to living material.

Publications

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Almeida D (2011) Electron transfer-induced fragmentation of thymine and uracil in atom-molecule collisions. in Physical chemistry chemical physics : PCCP

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Barc B (2014) Multi-photon and electron impact ionisation studies of reactivity in adenine-water clusters in International Journal of Mass Spectrometry

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Bockova J (2019) Mapping the complex metastable fragmentation pathways of excited 3-aminophenol+ in International Journal of Mass Spectrometry

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Eden S (2009) Electronic state spectroscopy of C2Cl4 in Chemical Physics

 
Description The exposure of living tissue to ionising radiation can initiate mutations or cancers, effects that can be traced to the modification of DNA. Although sophisticated models of radiation effects are available, considerable refinements are necessary to understand the underlying mechanisms on the molecular scale. As part of a major multi-disciplinary response to this challenge, this project was centred on probing the effects of the chemical environment on the excited state dynamics and fragmentation patterns of DNA bases and related biomolecules.

I developed a new apparatus at the OU for UV multi-photon ionisation (MPI) and electron impact ionisation (EII) experiments on DNA / RNA bases (adenine, thymine, cytosine, guanine and uracil) in isolation and in clusters (typically less than 10 molecules). This project provided the first experimental evidence for breaking the stable ring structure of isolated uracil by neutral electronic excitation, supporting an earlier theoretical prediction. Significantly, clustering with water protected the molecule from this radiation damage process. Another standout result was the observation of spontaneous reactivity in adenine-water clusters. These measurements demonstrate that any study of radiation interactions with fundamental biomolecules requires complementary research to assess the effects of intermolecular bonding before any strong conclusions can be made about biologically relevant processes.

In parallel with leading the OU experimental programme, I participated in complementary research at the Nuclear Physics Institute of Lyon (IPNL) and the New University of Lisbon (UNL). My IPNL work involved studying proton impact on DNA bases (analogising proton therapies), contributing to the development of an original multi-coincidence detection system, and measuring He atom collisions with mass-selected water and pyridine cluster ions. Results included the first demonstration of increased DNA base fragmentation in proton collisions involving electron-transfer. At UNL I participated in UV spectroscopy studies of biomolecules and the first experiments probing the fragmentation patterns of metastable DNA / RAN base anions produced in collisions with potassium atoms. As the outermost electron in potassium is weakly bound, these experiments provided an analogy for electron transfer from electronically excited neutrals in irradiated material.

This fellowship enabled me to construct a new MPI/EII facility and contribute to the development and exploitation of two unique collision experiments. The results have advanced our understanding of electron-transfer, ion impact, and UV-induced processes in DNA / RNA bases and clusters with applications in nanoscale radiation damage models.
Exploitation Route The exposure of living tissue to ionising radiation (photons, electrons, ions, and neutrals) can kill cells and initiate mutations or cancers, effects that can be traced to the modification of DNA. However, although sophisticated models of the effects of high-dose radiation exposure are available, considerable refinements are necessary to understand the underlying mechanisms on the molecular scale. As part of a major multi-disciplinary response to this challenge, my EPSRC LSI project was centred on probing the effects of hydrogen bonding on the valence electronic excited states, ionization energies, and fragmentation patterns of DNA bases and closely related biomolecules. From an applied perspective, the results can be integrated into Monte Carlo models [e.g. Friedland et al, Rad. Res.173 (2010 263] of radiation damage in biological material and guide radiotherapy innovations based on nanoscale understanding, for example using radio-sensitising dopants to enhance specific damage processes.
Sectors Chemicals,Pharmaceuticals and Medical Biotechnology

URL http://physics.open.ac.uk/clusters/multi.php
 
Description The project has been extremely fruitful in terms of research outputs. In addition to papers and conference contributions, the project played a key role in establishing the collaboration that led to the RABBIT doctoral training programme centred at the New University of Lisbon (described below). Furthermore, many of the absolute measurements from this collaboration are available in databases (e.g. http://www.science-softcon.de) that can be valuable in modelling atmospheric modelling or biological processes. The project was carried out within (and strengthened) an international multi-disciplinary research community (RADAM COST P9 Action, http://www.isa.au.dk/networks/cost/) that applies fundamental research in physical sciences to understand and quantify radiation damage in biological systems. This community has grown significantly since the fellowship, for example leading to the establishment of the Nano-IBCT Cost action (MP1002, http://fias.uni-frankfurt.de/nano-ibct/overview/) on Nanoscale insights into Ion Beam Cancer Therapy. I will collate more detailed data on the use of the project data in time for the next reporting period. However a good initial indicator of the value of the experimental measurements is the number of citations. The papers that have stemmed from this project have been cited 129 times (Web of Science, October 2014). Furthermore the fellowship led to me organising a conference at the Open University and enabled me to attract EU funding (Marie Curie Reintegration Grant). The laboratory facilities I built during the fellowship and the recognition that the scientific results gave me have provided the spring board for me to gain two subsequent EPSRC grants (EP/J002577/1 and EP/L002191/1), and Industrial sponsorship (Hiden Analytical). Paulo Limao-Vieira and I have contributed to training students from each other's groups in the regular visits between our labs. We have recently formalized this as the Open University is a participating international institution in the RABBIT (Radiation Biology and Biophysics) multi-disciplinary Doctoral training programme. In addition to the scientific benefits, this exchange-based student training programme has clear cultural benefits and can have impact on society though enabling talented young researchers to learn new skills and enhance professional links between the UK and in Portugal. My laboratory offers project opportunities to RABBIT students and I gave a talk at the recent RABBIT conference in Lisbon (24th June 2014). The EPSRC Life Sciences Interface project also enabled me to supervise a PhD student through to completion in 2012. The student (BB) subsequently used his skills to take an internship position at a UK telecommunications R&D company.
First Year Of Impact 2007
Sector Environment
Impact Types Societal

 
Description European Reintegration Grant
Amount € 45,000 (EUR)
Funding ID MERG-CT-2007-207292 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 02/2008 
End 01/2011
 
Description Claude Bernard University Lyon 1 
Organisation Claude Bernard University Lyon 1 (UCBL)
Country France 
Sector Academic/University 
PI Contribution During my Life Sciences Interface fellowship, I participated in research at the Nuclear Physics Institute of Lyon (IPNL) of Claude Bernard University Lyon 1. My IPNL work involved studying proton impact on DNA bases (analogising proton therapies), contributing to the development of an original multi-coincidence detection system, and measuring He atom collisions with mass-selected water and pyridine cluster ions. Results included the first demonstration of increased DNA base fragmentation in proton collisions involving electron-transfer. In addition to participating in measurements and experimental design / construction, I contributed to data analysis and writing papers.
Collaborator Contribution The Particle-Matter Interactions group (IPM, Farizon and co-workers) led all the experiments and development work described above. Farizon and co-workers were not directly involved in the other parts of my Life Sciences Interface fellowship research (based at the OU), although general discussions were useful.
Impact The most important outcomes of this research are the development of an original experimental system at IPNL and the measuring absolute cross sections for ion collisions with water and DNA bases than can be valuable in radiation track models. These are potentially valuable in medicine and hence society, although I am not yet aware of any direct use of these cross sections in medical models. Nonetheless, the value of absolute data is demonstrated by the fact that paper #2 in the list below has been cited 35 times since its publication in 2010. Collaborative refereed papers since my first EPSRC grant (2007): 1. A new experimental set-up designed for the investigation of irradiated nanosystems in the gas phase: the high intensity mass-and-energy selected cluster beam G. Bruny, S. Eden, S. Feil, R. Filliol, K. El Farkh, M.M. Harb, C. Teyssier, S. Ouaskit, H. Abdoul-Carime, B. Farizon, M. Farizon, T.D. Märk Rev. Sci. Instrum. 83 (2012) 013305 2. Absolute total and partial cross sections for ionization of nucleobases by proton impact in the Bragg Peak velocity range J. Tabet, S. Eden, S. Feil, H. Abdoul-Carime, B. Farizon, M. Farizon, S. Ouaskit, T.D. Märk Phys. Rev. A 82 (2010) 022703 3. Absolute molecular flux and angular distribution measurements to characterize DNA / RNA vapor jets J. Tabet, S. Eden, S. Feil, H. Abdoul-Carime, B. Farizon, M. Farizon, S. Ouaskit, T.D. Märk Nuclear Inst. and Methods in Physics Research B 268 (2010) 2458 4. Mass spectrometry (fragmentation ratios) of DNA base molecules following 80 keV proton impact with separation of electron capture and direct ionization processes J. Tabet, S. Eden, S. Feil, H. Abdoul-Carime, B. Farizon, M. Farizon, S. Ouaskit, T.D. Märk Int. J. Mass Spectrom. 292 (2010) 53 5. 20-150 keV proton-impact-induced ionization of uracil: fragmentation ratios and branching ratios for electron capture and direct ionization J. Tabet, S. Eden, S. Feil, H. Abdoul-Carime, B. Farizon, M. Farizon, S. Ouaskit, T.D. Märk Phys. Rev. A 81 (2010) 012711 6. Microscopic studies of atom-water collisions Z.P. Wang, P.M. Dinh, P.-G. Reinhard, E. Suraud, G. Bruny, C. Montano, S. Feil, S. Eden, H. Abdoul-Carime, B. Farizon, M. Farizon, S. Ouaskit, T.D. Märk Int. J. Mass Spectrom. 285 (2009) 143 7. Absolute partial cross sections for the destruction of H2 and H3+ in collisions with helium atoms at 50 and 60 keV / amu J. Tabet, S. Eden, F. Gobet, B. Farizon, M. Farizon, S. Ouaskit, T.D. Märk Int. J. Mass Spectrom. 272 (2008) 48
Start Year 2007
 
Description Universidade Nova de Lisboa (UNL) 
Organisation New University of Lisbon
Country Portugal 
Sector Academic/University 
PI Contribution I have collaborated with Paulo Limao-Vieira and co-workers at UNL for a number of years. I participate in UV spectroscopy studies of aeronomic and biological molecules as well as experiments probing the fragmentation patterns of metastable uracil anion produced in collisions with potassium atoms. As the outermost electron in potassium is weakly bound, these experiments provide an analogy for electron transfer from electronically excited neutrals in irradiated biological material. In addition to contributing to running experiments, my input includes data interpretations and writing papers. Reciprocally, Paulo Limao-Vieira contributes to our measurements and development work at the OU.
Collaborator Contribution Paulo Limao-Vieira's group lead the UV spectroscopy and electron transfer experiments described above. Paulo Limao-Vieira contributes to our measurements and development work through quite regular visits and remote discussions. These are mainly linked to data interpretation and experimental planning. Student exchanges between the groups have been supported through the RABBIT PhD training programme centred at UNL. I am currently supervising a student from UNL during a 6-month visit to carry out Stark deflection experiments at the OU.
Impact The collaboration has been extremely fruitful in terms of research outputs. In addition to papers (listed below) and conference contributions, the collaboration has played an important role in establishing the RABBIT doctoral training programme (described below). Furthermore, many of the absolute measurements from this collaboration are available in databases (http://www.science-softcon.de) that can be valuable in (for example) atmospheric modelling. Collaborative refereed papers since my first EPSRC grant (2007) 1. Electronic state spectroscopy of halothane as studied by ab initio calculations, vacuum ultraviolet (VUV) synchrotron radiation and electron scattering methods F. da Silva, D. Duflot, S. Hoffmann, N. Jones, F. Rodrigues, A. Ferreira- Rodrigues, B.G.G. de Souza, N.J. Mason, S. Eden, P. Limao-Vieira J. Phys. Chem. A 119 (2015) 8503 2. Multi-photon and electron impact ionisation studies of reactivity in adenine-water clusters B. Barc, M. Ryszka, J.-C. Poully, E. Jabbour Al Maalouf, Z. el Otell, J. Tabet, R. Parajuli, P.J.M. van der Burgt, P. Limão-Vieira, P. Cahillane, M. Dampc, N.J. Mason, S. Eden Int. J. Mass. Spectrom. 365-366 (2014) 194 3. New Fragmentation Pathways in K-THF Collisions as Studied by Electron Transfer Experiments: Negative Ion Formation D. Almeida, F. da Silva, S. Eden, G. Garcia, P. Limao-Vieira J. Phys. Chem. A 118 (2014) 690 4. Multi-photon ionization and fragmentation of uracil: neutral excited-state ring opening and hydration effects B. Barc, M. Ryszka, J. Spurrell, M. Dampc, P. Limão-Vieira, R. Parajuli, N.J. Mason, S. Eden J. Chem. Phys. 139 (2013) 244311 5. Mass spectrometry of anions and cations produced in 1-4 keV H-, O-, and OH- collisions with nitromethane, water, ethanol, and methanol D. Almeida, R. Antunes, G. Garcia, R. W. McCullough, S. Eden, P. Limão-Vieira Int. J. Mass. Spectrom. 311 (2012) 7 6. Electron transfer-induced fragmentation of thymine and uracil in atom- molecule collisions D. Almeida, R. Antunes, G. Martins, S. Eden, F. Ferreira da Silva, Y. Nunes, G. Garcia, P. Limão-Vieira Phys. Chem. Chem. Phys. 13 (2011) 15657 7. Electron transfer processes in potassium collisions with 5-fluorouracil and 5-chlorouracil [cited 6] F. Ferreira da Silva, D. Almeida, R. Antunes, G. Martins, Y. Nunes, S. Eden, G. Garcia, P. Limão-Vieira Phys. Chem. Chem. Phys. 13 (2011) 21621 8. Electronic state spectroscopy of C2Cl4 S. Eden, B. Barc, N. J. Mason, S.V. Hoffmann, Y. Nunes, P. Limão-Vieira Chem. Phys. 365 (2009) 150 9. Photoabsorption measurements and theoretical calculations of the electronic state spectroscopy of propionic, butyric, and valeric acids A. Vicente, R. Antunes, D. Almeida, I.J.A. Franco, S.V. Hoffmann, N.J. Mason, S. Eden, D. Duflot, J. Delwiche, M.-J. Hubin-Franskin, P. Limão-Vieira Phys. Chem. Chem. Phys. 11 (2009) 5729 10. Valence shell electronic spectroscopy of isoprene studied by theoretical calculations and by electron scattering, photoelectron, and absolute photoabsorption measurements G. Martins, A.M. Ferreira-Rodrigues, F.N. Rodrigues, G.G.B. de Souza, N.J. Mason, S. Eden, D. Duflot, J.-P. Flament, S.V. Hoffmann, J. Delwiche, M.-J. Hubin-Franskin, P. Limão-Vieira Phys. Chem. Chem. Phys. 11 (2009) 11219 11. The VUV electronic spectroscopy of acetone studied by synchrotron radiation M. Nobre, A. Fernandes, F. Ferreira da Silva, R. Antunes, D. Almeida, V. Kokhan, S.V. Hoffmann, N.J. Mason, S. Eden, P. Limão-Vieira Phys. Chem. Chem. Phys. 10 (2008) 550 12. VUV photoabsorption of CH3Cl and CH3I S. Eden, P. Limão-Vieira, S.V. Hoffmann, N.J. Mason Chem. Phys. 331 (2007) 232 Collaborative funding award: £1,000 British Council Treaty of Windsor Programme: collaborative experiments and student exchanges between the Open University and the New University of Lisbon in 2009 and 2010. Collaborative training programme: Paulo Limao-Vieira and I have contributed to training students from each other's groups in the regular visits between our labs. We have recently formalized this as the Open University is a participating international institution in the RABBIT (Radiation Biology and Biophysics) multi-disciplinary Doctoral training programme. In addition to the scientific benefits, this exchange-based student training programme has clear cultural benefits and can have impact on society though enabling talented young researchers to learn new skills and enhance professional links between the UK and in Portugal. My laboratory offers project opportunities to RABBIT students and I gave a talk at the recent RABBIT conference in Lisbon (24th June 2014).