First-principles simulations of the interaction of ionic projectiles with water and ice

Jorge Kohanoff

Atomistic Simulation CentreQueen’s University Belfast

Toulouse, 2-4 December 2009

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

IntroductionWhat 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

IntroductionConsequences 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

SSB DSB

Strand damage (backbone): cosmic rays, UV, X and -rays, ions, electrons):

Single strand beaks (SSB)

Double strand breaks (DSB, less than 10 units apart)

IntroductionEnergy 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: LINAC Hadrontherapy

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

RadicalsIons

fragments

Electrons generated by ionization

Secondary electrons

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?

Radical / ion dynamics

Generation of radicals,

ions, neutrals

Radical /ion transport

Biological end-point

effects

Modelling

AdiabaticTDDFT

Ehrenfest

First-principles MD Ehrenfest dynamics

Electron-molecule / condensed phase

simulations

Electron dynamics

Generation of electrons

Ion scattering

(loss)

Electron transport

Biological end-point

effects

X-ray diffraction

Experiment

Modelling

Molecular calculations

TDDFT Ehrenfestsimulations

Ehrenfest dynamics and

beyond

Electron spectroscopy

Mass spectroscopy

Electro-phoresis

Electron-molecule / condensed phase

simulations

electron-phonon interactions

Generation of reactive species

Electron energy distribution:

Peak at ~ 50 eV

Gustavo Garcia (Madrid)

Other species: radicals, ions, etc.

Abundance and energy distribution

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?

End-point biological effectsStrand 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)]

Ionic projectiles

Ionic projectileselectronic vs nuclear stopping

Stopping power: energy deposited per unit length (S=dE/dx)– Nuclear: dominates at low energies– Electronic:

Metals: for v0, S v (e-h pairs). Decrease a large v (Bethe) Insulators: Threshold due to band gap vth 0.10.2 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

Ionic projectilesRegions of interest for biomolecular systems

Water is an electronic insulator -- Eg (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.

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 methodsFirst-principles molecular dynamics

II

II R

VF

dt

RdM

2

2

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 methodsReal-time electronic dynamics

KSi

KSi Ht

i

)()(),( rtctr i

KSi HcS

c 1t

i

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 methodsEhrenfest dynamics

t-/2 t+/2t t+

r0=r1+V-1/2 V1/2=V-1/2+ F1/mV-1/2

t

Leap-frogCrank-Nic.Projections

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)

C through water slabv=0.1 a.u.

C through water slabv=0.1 a.u. (2.8 keV)

H2OO+2H

H2OOH+H

Head-on

Multiple dissociation

C through water slabv=0.075 a.u.

C through water slabv=0.05 a.u.

C through water slabv=0.05 a.u. (700 eV)

Continuous energy transfer

2H2O OH- + H3O+

C through water slabv=0.025 a.u.

Non-dissociative collisions. Energy transferred to vibrations.

C through water slabv=0.025 a.u. (175 eV)

Non-dissociative collisions.

Energy transfer to vibrations.

Complete stopping trajectories

C through water slabv=0.025 a.u.

Formation of new species: H2O2

C+ in watergeneration of new chemical species

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.

Adiabatic stopping Fragment distributions as a function of time

O˙/O-

H3O+

OH˙/OH-

H˙/H+

Adiabatic stoppingFragment 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 Åto

1 OH every 30 Å

O˙/O-

H3O+

C through solvated guaninev=0.1 a.u.

C through solvated guaninev=0.025 a.u.

Electronic stopping in ice

H+ shooting through channels in hexagonal ice (24 and 40 water molecules – 3 and 5 units)

Non-adiabatic stoppingchanneling of H+ through hexagonal ice

Energy transferred to electrons

Electronic stopping power channeling of H+ through hexagonal ice

• Se through center of channel is about half that of LiF

• Channels in ice are more open

• Se increases by a factor of 3 when proton travels closer to water molecules

Electronic stopping power channeling of H+ through hexagonal ice

Experiment: P. Bauer et al., NIMB 93, 132 (1994)Peak at 90 keV/nucleon

Non-adiabatic stoppingCharge 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+.

Electronic stopping in metals

SRIM stopping tables reproduced !

Nuclear materials: stopping of Fe in Fe

It is possible to compute Se for heavier projectiles

FM vs PM: influence of EDOS apart from

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 (H2O2 ) 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.

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)

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

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)

IntroductionThe 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

IntroductionConsequences 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 repairDSB: 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.

IntroductionMorphology 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)

SSB DSB

IntroductionSources of radiation

IONS

ELECTRONS

PHOTONS

NEUTRONS

IntroductionRadiotherapies

X-ray therapy: LINAC Hadrontherapy: CYCLOTRON

UK

Proton therapy facility at Clatterbridge (Merseyside)

ExperimentalLow 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)

ExperimentalTowards 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)

IntroductionSources of radiation: electromagnetic (photons)

Photon momentum is small. Cannot produce impact fragmentation like atoms or ions.

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 throughbiological matter

radicals

New radiotherapies (Belfast)

Adiabatic stoppingAngular distributions

Final dispersion angle increases and spreads out for decreasing projectile energy

Adiabatic stoppingDistribution of swift secondary particles

Non-adiabatic stoppingsome tests

Test of ghost orbitals Test of de-centering