Modeling proton-induced damage on 2-deoxy-D-ribose. Conformational analysis.

Modeling proton-induced damage in biological systems, in particular in DNA building blocks, is of major concern in studies on cancer proton therapy. This is indeed an extremely complex process and analysis of the mechanism at the molecular level is of crucial interest. Such collision reactions of protons on biological targets induce different reactions: excitation and ionization of the biomolecule, fragmentation of the ionized species, and charge transfer from the projectile ion toward the biomolecular target. In order to have an insight into such mechanisms, we have performed a theoretical approach of two of the most important steps, the fragmentation and the charge transfer processes. For that purpose, we have considered collision of protons with isolated 2-deoxy-D-ribose by means of ab-initio molecular dynamics and quantum chemistry molecular methods. The conformation of the sugar moiety has been analyzed and appears to induce important effects, in particular different fragmentation patterns have been pointed out with regard to the conformation, and significant variations of the charge transfer cross sections have been exhibited.

Ultrafast nonadiabatic fragmentation dynamics of doubly charged uracil in a gas phase.

A combination of time-dependent density functional theory and Born-Oppenheimer molecular dynamics methods is used to investigate fragmentation of doubly charged gas-phase uracil in collisions with 100 keV protons. The results are in good agreement with ion-ion coincidence measurements. Orbitals of similar energy and/or localized in similar bonds lead to very different fragmentation patterns, thus showing the importance of intramolecular chemical environment. In general, the observed fragments do not correspond to the energetically most favorable dissociation path, which is due to dynamical effects occurring in the first few femtoseconds after electron removal.

Theoretical investigation of the ultrafast dissociation of ionised biomolecules immersed in water: direct and indirect effects.

Theoretical simulations are particularly well suited to investigate, at a molecular level, direct and indirect effects of ionising radiations in DNA, as in the particular case of irradiation by swift heavy ions such as those used in hadron therapy. In the past recent years, we have developed the modeling at the microscopic level of the early stages of the Coulomb explosion of DNA molecules immersed in liquid water that follows the irradiation by swift heavy ions. To that end, Time-Dependent Density Functional Theory molecular dynamics simulations (TD-DFT MD) have been developed where localised Wannier orbitals are propagated. This latter enables to separate molecular orbitals of each water molecule from the molecular orbitals of the biomolecule. Our main objective is to demonstrate that the double ionisation of one molecule of the liquid sample, either one water molecule from the solvent or the biomolecule, may be in some cases responsible for the formation of an atomic oxygen as a direct consequence of the molecule Coulomb explosion. Our hypothesis is that the molecular double ionisation arising from irradiation by swift heavy ions (about 10% of ionisation events by ions whose velocity is about the third of speed of light), as a primary event, though maybe less probable than other events resulting from the electronic cascading (for instance, electronic excitations, electron attachments), may be systematically more damageable (and more lethal), as supported by experiments that have been carried out in our group in the 1990s (in studies of damages created by K holes in DNA). The chemical reactivity of the produced atomic oxygen with other radicals present in the medium will ultimately lead to chemical products that are harmful to DNA. In the present paper, we review our theoretical methodology in an attempt that the community be familiar with our new approach. Results on the production of atomic oxygen as a result of the double ionisation of water or as a result of the double ionisation of the Uracil RNA base will be presented.

Absolute charge transfer and fragmentation cross sections in He2+-C60 collisions.

We have determined absolute charge transfer and fragmentation cross sections in He2++C60 collisions in the impact-energy range 0.1-250 keV by using a combined experimental and theoretical approach. We have found that the cross sections for the formation of He+ and He0 are comparable in magnitude, which cannot be explained by the sole contribution of pure single and double electron capture but also by contribution of transfer-ionization processes that are important even at low impact energies. The results show that multifragmentation is important only at impact energies larger than 40 keV; at lower energies, sequential C2 evaporation is the dominant process.

Strand breaks induced in plasmid DNA by ultrasoft X-rays: influence of hydration and packing.

PURPOSE: To study the effect of hydration level and plasmid packing on strand break induction in DNA by ultrasoft X-ray. MATERIALS AND METHODS: Bluescript (pBS, tight packing) and pSP189 (pSP, loose packing) plasmids were irradiated by 250, 380, and 760 eV ultrasoft X-rays at the Laboratoire pour l'Utilisation du Rayonnement Electromagnétique synchrotron facility (Orsay, France). Single and double strand breaks (SSB and DSB) were quantified by gel electrophoresis. RESULTS: The number of DSB per Gray and per Dalton in pBS plasmids were (5.6 +/- 0.1), (6.3 +/- 0.1) and (8.5 +/- 0.4)x10(-12) at 250, 380 and 760 eV, respectively. They were respectively 1.4 +/- 0.1, 1.1 +/- 0.1 and 1.9 +/- 0.2 times larger for pSP plasmids. SSB/DSB ratios varied between 4.4 and 6.4. CONCLUSION: The observed dependency of strand break induction by ultrasoft X-rays on the hydration level of DNA in plasmids films may be associated with: (i) Damage transfer from the water shell to the DNA and/or (ii) change in packing. 760 eV photons which are more often absorbed in the hydration shell and yield longer range electrons than 250 and 380 eV photons, induce more DSB per Gray and per Dalton, especially for the looser plasmid (pSP).

A Monte Carlo code for the simulation of heavy-ion tracks in water.

TILDA, a new Monte Carlo track structure code for ions in gaseous water that is valid for both high-LET (approximately 10(4) keV/microm) and low-LET ions, is presented. It is specially designed for a comparison of the patterns of energy deposited by a large range of ions. Low-LET ions are described in a perturbative frame, whereas heavy ions with a very high stopping power are treated using the Lindhard local density approximation and the Russek and Meli statistical method. Ionization cross sections singly differential with energy compare well with the experiment. As an illustration of the non-perturbative interaction of high-LET ions, a comparison between the ion tracks of light and heavy ions with the same specific energy is presented (1.4 MeV/nucleon helium and uranium ions). The mean energy for ejected electrons was found to be approximately four times larger for uranium than for helium, leading to a much larger track radius in the first case. For electrons, except for the excitation cross sections that are deduced from experimental fits, cross sections are derived analytically. For any orientation of the target molecule, the code calculates multiple differential cross sections as a function of the ejection and scattering angles and of the energy transfer. The corresponding singly differential and total ionization cross sections are in good agreement with experimental data. The angular distribution of secondary electrons is shown to depend strongly on the orientation of the water molecule.

Chromosome aberrations and cell inactivation induced in mammalian cells by ultrasoft X-rays: correlation with the core ionizations in DNA.

PURPOSE: To study the frequency of chromosome aberrations induced by soft X-rays. To see if the core ionization of DNA atoms is involved in this end-point as much as it appears to be in cell killing. MATERIALS AND METHODS: V79 hamster cells were irradiated by synchrotron radiation photons iso-attenuated in the cell (250, 350, 810eV). The morphological chromosome aberrations detected in the first post-irradiation cell division (dicentrics and centric rings) were studied by Giemsa staining. RESULTS: The chromosome aberrations at 350eV were, respectively, 2.6 +/- 0.8 and 2.1 +/- 0.8 times more numerous than at 250 and 810eV for the same average dose absorbed by the nucleus. These relative effectivenesses are comparable with the ones already measured for cell killing. Moreover, they roughly vary such as the relative numbers of core ionizations (including in the phosphorus L-shell) produced in DNA and its bound water (water being involved only at 810eV through the oxygen atoms). In particular, they reproduce the characteristic twofold enhancement at 350eV, above the carbon K threshold. CONCLUSIONS: Correlations suggest that the core ionization process is likely a common and essential mechanism initiating both chromosome aberration and cell killing end-points at these photon energies.

Charge transfer and dissociation in collisions of metal clusters with atoms.

We present a combined theoretical and experimental study of charge transfer and dissociation in collisions of slow Li31(2+) clusters with Cs atoms. We provide a direct quantitative comparison between theory and experiment and show that good agreement is found only when the exact experimental time of flight and initial cluster temperature are taken into account in the theoretical modeling. We demonstrate the validity of the simple physical image that consists in explaining evaporation as resulting from a collisional energy deposit due to cluster electronic excitation during charge transfer.

Biological effects induced by K photo-ionisation in and near constituent atoms of DNA.

In order to assess the lethal efficiency and other biological effects of inner shell ionisations of constituent atoms of DNA ('K' events), experiments were developed at the LURE synchrotron facility using ultrasoft X rays as a probe of K events. The lethal efficiency of ultrasoft X rays above the carbon K threshold was especially investigated using V79 cells and compared with their efficiency to induce double strand breaks in dry plasmid-DNA. A correlation between the K event efficiencies for these processes is shown. Beams at 340 eV were found to be twice as efficient at killing cells than were beams at 250 eV. In addition, a rough two-fold increase of the relative biological effectiveness for dicentric + ring induction has also been observed between 250 and 340 eV radiations.

Cell inactivation and double-strand breaks: the role of core ionizations, as probed by ultrasoft X rays.

The large RBE (approximately 7) measured for the killing of Chinese hamster V79 cells by 340 eV ultrasoft X rays, which preferentially ionize the K shell of carbon atoms (Hervé du Penhoat et al., Radiat. Res. 151, 649-658, 1999), was used to investigate the location of sensitive sites for cell inactivation and the physical modes of action of radiation. The enhancement of the RBE above the carbon K-shell edge either may indicate a high intrinsic efficiency of carbon K-shell ionizations (due, for example, to a specific physical or chemical effect) or may be related to the preferential localization of these ionizations on the DNA. The second interpretation would indicate a strong local (within 3 nm) action of K-shell ionizations and consequently the importance of a direct mechanism for radiation lethality (without excluding an action in conjunction with an indirect component). To distinguish between these two hypotheses, the efficiencies of core ionizations in DNA atoms (phosphorus L-shell, carbon K-shell, and oxygen K-shell ionizations) to induce damages were investigated by measuring their capacities to produce DNA double-strand breaks (DSBs). The effect of photoionizations in isolated DNA was studied using pBS plasmids in a partially hydrated state. No enhancement of the efficiency of DSB induction by carbon K-shell ionizations compared to oxygen K-shell ionizations was found, supporting the hypothesis that it is the localization of these carbon K-shell events on DNA which gives to the 340 eV photons their high killing efficiency. In agreement with this interpretation, cell inactivation and DSB induction, which do not appear to be correlated when expressed in terms of yields per unit dose in the sample, exhibit a rather good correlation when expressed in terms of efficiencies per core event in the DNA. These results suggest that core ionizations in DNA, through core-hole relaxation in conjunction with localized effects of spatially correlated secondary and Auger electrons, may be the major critical events for cell inactivation, and that the resulting DSBs (or a constant fraction of these DSBs) may be a major class of unrepairable lesions.