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First-principles simulations of the interaction of ionic projectiles with water and ice Jorge Kohanoff Atomistic Simulation Centre Queen’s University Belfast Toulouse, 2-4 December 2009
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Contents Introduction Main questions General framework Computational methods Results: – C through water – C through solvated guanine – H + through ice – H + through metals, self-irradiation in metals. Conclusions and Outlook
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Introduction What does radiation do to biomolecules? Radiation causes lesions to biomolecules, especially DNA (but also proteins) – Directly by interacting with DNA components (bases, sugars or backbone) – Indirectly by interacting with matter around DNA and generating reactive species that cause the damage, e.g. electrons by ionization free radicals (OH˙), e.g. from water
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Introduction Consequences of DNA damage Mainly two effects: To alter of eliminate the ability of cells to replicate – Senescence (dormancy) – Apoptosis (cell suicide) To induce potentially harmful mutations – Cancerous tumors DNA damage occurs at a rate of 1,000 to 1,000,000 molecular lesions per cell per day SSB: easy to repair DSB: can go wrong in many ways ACCUMULATION OF DSB TRIGGERS CYCLE CELL ARREST USEFUL IN CANCER THERAPY SSBDSB Strand damage (backbone): cosmic rays, UV, X and -rays, ions, electrons): Single strand beaks (SSB) Double strand breaks (DSB, less than 10 units apart)
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Introduction Energy deposition and radiotherapies X-rays and electrons deposit energy along the way with decreasing intensity Ions deposit mostly at the Bragg peak X-ray therapy: LINACHadrontherapy
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Transport through water / biological matter Established radiotherapies X-rays DNA Attachment to DNA and strand breaking Cellular membrane Ions (p +,C + ) Electrons generated by ionization Radicals Ions fragments Electrons generated by ionization Secondary electrons
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Main questions Which particles cause DNA damage? Where do they come from? – Primary events (high energy): Direct DNA ionization Direct impact fragmentation – Secondary events (low energy): Electrons generated by ionization of surrounding material Radicals (e.g. OH˙, H˙) generated in collision processes Fragments (ions/neutrals) generated in primary processes What is the origin of double strand breaks?
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Radical / ion dynamics Generation of radicals, ions, neutrals Radical /ion transport Biological end-point effects Modelling Adiabatic TDDFT Ehrenfest First-principles MD Ehrenfest dynamics Electron-molecule / condensed phase simulations
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Electron dynamics Generation of electrons Ion scattering (loss) Electron transport Biological end-point effects X-ray diffraction Experiment Modelling Molecular calculations TDDFT Ehrenfest simulations Ehrenfest dynamics and beyond Electron spectroscopy Mass spectroscopy Electro- phoresis Electron-molecule / condensed phase simulations electron-phonon interactions
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Generation of reactive species Electron energy distribution: Peak at ~ 50 eV Gustavo Garcia (Madrid) Other species: radicals, ions, etc. Abundance and energy distribution
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Inelastic transport of electrons and radicals How far do electrons/radicals travel in water? (Mean free path) How far do electrons/radical travel in intracellular matter water/protein/ions mixture -- histones What type of processes stop electrons? impact ionization, electron-phonon interactions What type of processes stop radicals? What secondary species are generated along the tracks? What is their frequency and energy distribution?
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End-point biological effects Strand breaks by low energy electrons and ions B. Boudaïffa et al, Science 287, 1659 (2000) P. Swiderek, Angew. Chem. Int.. Ed. 45, 4056 (2006) B. Liu et al., J. Chem. Phys. 128, 075102 (2008) Low energy electrons (1-20 eV) cause SSB and DSB in plasmid DNA Dissociative electron attachment to DNA components or hydration waters (electronic resonances) Low energy C + ions (1-6 keV) also cause SSB and DSB in plasmid DNA [A. Hunniford et al., Phys. Med. Biol. 52, 3729 (2007)]
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Ionic projectiles
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Ionic projectiles electronic vs nuclear stopping Stopping power: energy deposited per unit length (S=dE/dx) – Nuclear: dominates at low energies – Electronic: Metals: for v 0, S v (e-h pairs). Decrease a large v (Bethe) Insulators: Threshold due to band gap v th 0.1 0.2 a.u. [First-principles on LiF: M. Pruneda et al., Phys. Rev. Lett. 99, 235501 (2007)] Schiefermuller et al., Phys. Rev. A 48, 4467 (1993) Cabrera-Trujillo et al., Phys. Rev. Lett. 84, 5300 (2000) nuclear electronic
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Ionic projectiles Regions of interest for biomolecular systems Water is an electronic insulator -- E g (water) 10 eV. – Threshold effects separate nuclear from electronic stopping. Low and high energy regimes can be treated separately Low energy (v < 0.1 a.u., or 4 keV for C): adiabatic regime (GS electrons) High energy (v > 0.1 a.u.): sudden regime (purely electronic dynamics) Depending on the energy levels of the projectile: – Electronic excitation, capture and ionization by low-energy ions is possible. Intermediate energy: impact fragmentation coexists with electronic excitation. Combined electron-nuclear dynamics required.
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Adiabatic regime – First-principles molecular dynamics (Car-Parrinello) – Electronic structure described within DFT-GGA – Pseudopotentials for core electrons – Slab geometry to avoid PBC in the incidence direction – Charge state of projectile not relevant under adiabatic conditions SIESTA code [ J. M. Soler, E. Artacho, J. D. Gale, A. Garcia, J. Junquera, P. Ordejon & D. Sanchez- Portal, J. Phys.: Condens. Matter 14, 2745 (2002)] – Basis set for electronic wave functions: numerical atomic orbitals – Numerical evaluation of matrix elements – Nuclear motion described by Newton’s equations: Computational methods First-principles molecular dynamics
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Sudden regime – Real-time electronic dynamics via TDDFT – Adiabatic GGA (AGGA) approximation to time-dependent XC – Fixed nuclei – Incident ion treated as a moving external potential – Channeling to avoid direct impact Time-dependent Kohn-Sham equations implemented in SIESTA [A. Tsolakidis, D. Sanchez-Portal and R. M. Martin, Phys. Rev. B 66, 235416 (2002)] with Kohn-Sham orbitals expanded in atomic orbital basis Computational methods Real-time electronic dynamics
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Sudden regime – Real-time electronic dynamics via TDDFT – Adiabatic GGA (AGGA) approximation to time-dependent XC – Classical MD for the nuclei – Incident ion treated as another classical particle – No channeling restrictions Ehrenfest equations implemented in SIESTA [D. Sanchez-Portal, J. Kohanoff and E. Artacho (unpublished)] Computational methods Ehrenfest dynamics t- /2t+ /2 t t+ r 0 =r 1 + V -1/2 V 1/2 =V -1/2 + F 1 /m V -1/2 tt Leap-frog Crank-Nic. Projections
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Systems studied Adiabatic – C passing through water slab (128 water molecules) – C passing through guanine solvated in water slab (methylguanine + 136 water molecules) Sudden – H + shooting through channels in hexagonal ice (24 and 40 water molecules)
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C through water slab v=0.1 a.u.
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C through water slab v=0.1 a.u. (2.8 keV) H 2 O O+2H H 2 O OH+H Head-on Multiple dissociation
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C through water slab v=0.075 a.u.
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C through water slab v=0.05 a.u.
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C through water slab v=0.05 a.u. (700 eV) Continuous energy transfer 2H 2 O OH - + H 3 O +
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C through water slab v=0.025 a.u. Non-dissociative collisions. Energy transferred to vibrations.
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C through water slab v=0.025 a.u. (175 eV) Non-dissociative collisions. Energy transfer to vibrations. Complete stopping trajectories
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C through water slab v=0.025 a.u. Formation of new species: H 2 O 2
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C + in water generation of new chemical species
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Adiabatic stopping (nuclear) Final kinetic energy distributions Average loss of kinetic energy (nuclear stopping) peaks at about 0.08 a.u. Mostly elastic. Interplay between cross section and energy transfer. At low energies also vibrational excitation of OH stretching.
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Adiabatic stopping Fragment distributions as a function of time O˙/O - H3O+H3O+ OH˙/OH - H˙/H +
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Adiabatic stopping Fragment distributions as a function of position Low-energy projectiles cause more damage ! H˙/H + 1 H every 5 Å to 1 H every 20 Å OH˙/OH - 1 OH every 7 Å to 1 OH every 30 Å O˙/O - H3O+H3O+
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C through solvated guanine v=0.1 a.u.
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C through solvated guanine v=0.025 a.u.
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Electronic stopping in ice H + shooting through channels in hexagonal ice (24 and 40 water molecules – 3 and 5 units)
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Non-adiabatic stopping channeling of H + through hexagonal ice Energy transferred to electrons
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Electronic stopping power channeling of H + through hexagonal ice S e through center of channel is about half that of LiF Channels in ice are more open S e increases by a factor of 3 when proton travels closer to water molecules
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Electronic stopping power channeling of H + through hexagonal ice Experiment: P. Bauer et al., NIMB 93, 132 (1994) Peak at 90 keV/nucleon
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Non-adiabatic stopping Charge state of the proton At low speed the proton drags the electronic charge with it, forming H. At higher speed, electrons respond to the proton, but too late, creating a wake. Eventually, the electronic wake detaches and the proton travels as H +.
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Electronic stopping in metals SRIM stopping tables reproduced !
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Nuclear materials: stopping of Fe in Fe It is possible to compute S e for heavier projectiles FM vs PM: influence of EDOS apart from
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Conclusions Nuclear and electronic stopping in water separated in energy. Nuclear stopping becomes unimportant at v 0.15 - 0.2 a.u., where electronic stopping begins. Peak in nuclear stopping Formation of new chemical species (e.g. formic acid) H, O and OH species are created by water radiolysis. Also hydrogen peroxide (H 2 O 2 ) observed. Spatial rate of production increases with decreasing speed. Hyperthermal fragments. No thermalization of the medium. Charge state: hyperthermal H, otherwise H + Threshold of 0.2 a.u. for electronic stopping in ice. Maximum at 80 kev/n Strong channeling effects.
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Wish list: radicals and ions Generation of reactive species (radicals, ions) by ions, X-rays and electrons. Ehrenfest dynamics, R. Vuilleumiere. How do radicals and ions make it to DNA? First-principles Molecular Dynamics (Car-Parrinello). SIC functional. Radical attack to DNA (Mundy, Eriksson)
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Wish list: electrons Inelastic transport of electrons through water and biological matter at energies below 50 eV (beyond Ehrenfest dynamics) – Electron impact ionization – Electronic excitation Capture of electrons in resonant states of biomolecules in realistic environments: nucleic acids, sugars, nucleosides, nucleotides and DNA fragments, solvated or wrapped around histones. Electron transport to other regions in DNA, e.g. phosphate bonds. Weakening of bonds and strand breaks: Dynamics of dissociative electron attachment. Exchange-correlation functionals: hybrids vs SIC (Suraud, Gervasio) Thanks to: YOU FOR YOUR ATTENTION Wellcome Trust for financial support and Clare Hall for visiting fellowship Department of Earth Sciences (University of Cambridge) for hospitality M. Smyth
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Collaborators Emilio Artacho (Cambridge, UK) Daniel Sanchez-Portal (San Sebastian, Spain) … and thanks to Pablo Dans Puiggrós (Montevideo, Uruguay) Mariví Fernández-Serra (Stonybrook, USA) Tristan Youngs (QUB, Northern Ireland) Kostya Trachenko (Cambridge, UK)
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Introduction The origins of radiation damage and therapy Wilhelm Röntgen (Würzburg, 1895): discovers X-rays and proposes medical uses. John Hall-Edwards (Birmingham, 1896): first radiograph for diagnostic purposes. Experiments on his own arm and contracts dermatitis. If they cause harm, they can also cure L. Freund (Vienna, 1898): first therapeutic use of X-rays (birthmark removal). J. E. Gilman (Chicago, 1901): first use of X- rays in cancer therapy. Widespread use of radiotherapy for cancer only after WW2
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Introduction Consequences of DNA damage Mainly two effects: – To alter of eliminate the ability of cells to replicate Senescence (dormancy) Apoptosis (cell suicide) Cancerous tumours – To induce potentially harmful mutations DNA damage, due to environmental factors and normal metabolic processes, occurs at a rate of 1,000 to 1,000,000 molecular lesions per cell per day Something has to be done! SSB: easy to repair DSB: can go wrong in many ways. ACCUMULATION OF DSB triggers multiple pathways such as cell cycle arrest and inhibition of cell division: USEFUL IN CANCER THERAPY.
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Introduction Morphology and sources of DNA damage Types of damage – Bases loss or changes (thermal) Dimerization (UV-B, direct) – Inter-strand H-bond breakage Cross-linking (chemicals) – Intra-strand (backbone) cosmic rays, UV-A indirectly, X and -rays, ions, electrons): Single strand beaks (SSB, thermal) Double strand breaks (DSB, less than 10 units apart) SSBDSB
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Introduction Sources of radiation IONS ELECTRONS PHOTONS NEUTRONS
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Introduction Radiotherapies X-ray therapy: LINAC Hadrontherapy: CYCLOTRON UK Proton therapy facility at Clatterbridge (Merseyside)
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Experimental Low energy ions: gas-phase fragmentation Gas phase: complete fragmentation of nucleobases and sugars. Charge effects, and HCN as dominant channel F. Alvarado et al., PCCP 8, 1922 (2006); J. Chem. Phys. 127, 034301 (2007) T. Schlathölter et al., Phys. Scr. 73, C113 (2006)
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Experimental Towards realistic environments: microsolvation Microsolvation: fragmentation of a hydrated nucleotide (adenosine monophosphate, AMP) by 50 keV Na atoms. Water protects the nucleotide (evaporation) Selective loss of H atom (base or sugar?) B. Liu et al., Phys. Rev. Lett. 97, 133401 (2007); J. Chem. Phys. 128, 075102 (2008)
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Introduction Sources of radiation: electromagnetic (photons) Photon momentum is small. Cannot produce impact fragmentation like atoms or ions.
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Secondary electrons Transport through: Metal Coating Biological matter X-rays Coated Au nanoparticle DNA Electrons generated in Auger processes Attachment to DNA and strand breaking Cellular membrane Laser Ions (p + ) Electrons generated by ionization Transport through biological matter radicals New radiotherapies (Belfast)
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Adiabatic stopping Angular distributions Final dispersion angle increases and spreads out for decreasing projectile energy
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Adiabatic stopping Distribution of swift secondary particles
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Non-adiabatic stopping some tests Test of ghost orbitalsTest of de-centering
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