Binding preference of nitroimidazolic radiosensitizers to nucleobases and nucleosides probed by electrospray ionization mass spectrometry and density functional theory.

Nitroimidazolic radiosensitizers are used in radiation therapy to selectively sensitize cancer cells deprived of oxygen, and the actual mechanism of radiosensitization is still not understood. Selecting five radiosensitizers (1-methyl-5-nitroimidazole, ronidazole, ornidazole, metronidazole, and nimorazole) with a common 5-nitroimidazolic ring with different substitutions at N1 and C2 positions of the imidazole moiety, we investigate here their binding to nucleobases (A, T, G, and C) and nucleosides (As, Td, Gs, and Cd) via the positive electrospray ionization mass spectrometry experiments. In addition, quantum chemical calculations at the M062x/6-311+G(d,p) level of theory and basis set were used to determine binding energies of the proton bound dimers of a radiosensitizer and a nucleobase. The positive electrospray ionization leads to the formation of proton bound dimers of all radiosensitizers except 1-methyl-5-nitroimidazole in high abundance with C and smaller abundance with G. Ronidazole and metronidazole formed less abundant dimers also with A, while no dimers were observed to be formed at all with T. In contrast to the case of the nucleoside Td, the dimer intensity is as high as that with Cd, while the abundance of the dimer with Gs is smaller than that of the former. The experimental results are consistent with the calculations of binding energies suggesting proton bound dimers with C and G to be the strongest bound ones. Finally, a barrier-free proton transfer is observed when protonated G or C approaches the nitroimidazole ring.

Maxwell-Boltzmann versus non-ergodic events in the velocity distribution of water molecules evaporated from protonated water nanodroplets.

Measurement of velocity distributions of evaporated water monomers from small mass- and energy-selected protonated water clusters allows probing the extent of thermalization after excitation of these ultimately small nanodroplets. Electronic excitation of a molecule in the cluster is here induced by a single collision with an argon atom in the keV energy range. The measured velocity distributions of the departing neutral molecules exhibit bimodal shapes with a lower-velocity part consistent with a complete redistribution of the deposited energy in the entire cluster and a higher-velocity contribution corresponding to evaporation before complete energy redistribution. Statistical molecular dynamics calculations reproduce the bimodal shape of the velocity distributions by assuming an initial spreading of the excitation energy among all modes, thereby reproducing the lower velocity contribution of the distribution. By contrast, assuming the deposited energy to be initially localized among the modes of a single molecule leads to calculated distributions with two components whose shape is in accordance with the experimental results. The characteristics and the relative abundance of these two contributions in the velocity distributions obtained are presented and discussed as a function of the number of molecules (n = 2-10) in the ionized nanodroplet H+(H2O) n .

Sequential evaporation of water molecules from protonated water clusters: measurement of the velocity distributions of the evaporated molecules and statistical analysis.

Velocity distributions of neutral water molecules evaporated after collision induced dissociation of protonated water clusters H+(H2O)n≤10 were measured using the combined correlated ion and neutral fragment time-of-flight (COINTOF) and velocity map imaging (VMI) techniques. As observed previously, all measured velocity distributions exhibit two contributions, with a low velocity part identified by statistical molecular dynamics (SMD) simulations as events obeying the Maxwell-Boltzmann statistics and a high velocity contribution corresponding to non-ergodic events in which energy redistribution is incomplete. In contrast to earlier studies, where the evaporation of a single molecule was probed, the present study is concerned with events involving the evaporation of up to five water molecules. In particular, we discuss here in detail the cases of two and three evaporated molecules. Evaporation of several water molecules after CID can be interpreted in general as a sequential evaporation process. In addition to the SMD calculations, a Monte Carlo (MC) based simulation was developed allowing the reconstruction of the velocity distribution produced by the evaporation of m molecules from H+(H2O)n≤10 cluster ions using the measured velocity distributions for singly evaporated molecules as the input. The observed broadening of the low-velocity part of the distributions for the evaporation of two and three molecules as compared to the width for the evaporation of a single molecule results from the cumulative recoil velocity of the successive ion residues as well as the intrinsically broader distributions for decreasingly smaller parent clusters. Further MC simulations were carried out assuming that a certain proportion of non-ergodic events is responsible for the first evaporation in such a sequential evaporation series, thereby allowing to model the entire velocity distribution.

Correlated ion and neutral time of flight technique combined with velocity map imaging: Quantitative measurements for dissociation processes in excited molecular nano-systems.

The combination of the Dispositif d'Irradiation d'Agrégats Moléculaire with the correlated ion and neutral time of flight-velocity map imaging technique provides a new way to explore processes occurring subsequent to the excitation of charged nano-systems. The present contribution describes in detail the methods developed for the quantitative measurement of branching ratios and cross sections for collision-induced dissociation processes of water cluster nano-systems. These methods are based on measurements of the detection efficiency of neutral fragments produced in these dissociation reactions. Moreover, measured detection efficiencies are used here to extract the number of neutral fragments produced for a given charged fragment.

Measurement of the velocity of neutral fragments by the "correlated ion and neutral time of flight" method combined with "velocity-map imaging".

In the challenging field of imaging molecular dynamics, a novel method has been developed and implemented that allows the measurement of the velocity of neutral fragments produced in collision induced dissociation experiments on an event-by-event basis. This has been made possible by combining a correlated ion and neutral time of flight method with a velocity map imaging technique. This new method relies on a multiparametric correlated detection of the neutral and charged fragments from collision induced dissociation on one single detector. Its implementation on the DIAM device (Device for irradiation of biomolecular clusters) (Dispositif d'Irradiation d'Agrégats bioMoléculaires) allowed us to measure the velocity distribution of water molecules evaporated from collision induced dissociation of mass- and energy-selected protonated water clusters.

A novel "correlated ion and neutral time of flight" method: event-by-event detection of neutral and charged fragments in collision induced dissociation of mass selected ions.

A new tandem mass spectrometry (MS/MS) method based on time of flight measurements performed on an event-by-event detection technique is presented. This "correlated ion and neutral time of flight" method allows to explore Collision Induced Dissociation (CID) fragmentation processes by directly identifying not only all ions and neutral fragments produced but also their arrival time correlations within each single fragmentation event from a dissociating molecular ion. This constitutes a new step in the characterization of molecular ions. The method will be illustrated here for a prototypical case involving CID of protonated water clusters H(+)(H2O)n = 1-5 upon collisions with argon atoms.

A new experimental setup designed for the investigation of irradiation of nanosystems in the gas phase: a high intensity mass-and-energy selected cluster beam.

DIAM (Dispositif d'Irradiation d'Agrégats Moléculaires) is a new experimental setup devoted to investigate processes induced by irradiation at the nanoscale. The DIAM apparatus is based on a combination of techniques including a particle beam from high-energy physics, a cluster source from molecular and cluster physics, and mass spectrometry form analytical sciences. In this paper, we will describe the first part of the DIAM apparatus that consists of an ExB double spectrometer connected to a cluster ion source based on a continuous supersonic expansion in the presence of ionizing electrons. This setup produces high intensities of energy-and-mass selected molecular cluster ion beams (1000 s of counts s(-1)). The performance of the instrument will be shown through measurements of 6-8 keV beams of protonated water clusters, (H(2)O)(n)H(+) (n = 0-21) and mixed protonated (or deprotonated) water-pyridine cluster ions: PyrH(+)(H(2)O)(n) (n = 0-15), Pyr(2)H(+) (H(2)O)(n) (n = 0-9), and (Pyr-H)(+) (H(2)O).

Electron attachment to uracil: effective destruction at subexcitation energies.

We demonstrate that electrons at energies below the threshold for electronic excitation (<3 eV) effectively decompose gas phase uracil generating a mobile hydrogen radical and the corresponding closed shell uracil fragment anion (U-H)(-). The reaction is energetically driven by the large electron affinity of the (U-H) radical. This observation has significant consequences for the molecular picture of radiation damage, i.e., genotoxic effects or damage of living cells due to the secondary component of high energy radiation.

Direct experimental evidence for a negative heat capacity in the liquid-to-gas phase transition in hydrogen cluster ions: backbending of the caloric curve.

By selecting specific decay reactions in high-energy collisions (60 keV/amu) of hydrogen cluster ions with a helium target (utilizing event-by-event data of a recently developed multicoincidence experiment) and by deriving corresponding temperatures for these microcanonical cluster ensembles (analyzing respective fragment distributions), we are able to construct caloric curves for H+3(H2)(m) cluster ions (6

Probing the liquid-to-gas phase transition in a cluster via a caloric curve.

High-energy collisions ( 60 keV/amu) of hydrogen cluster ions with a helium target have been completely analyzed on an event-by-event basis. By selecting specific decay reactions we can start after the energizing collision with a microcanonical cluster ion ensemble of fixed excitation energy and we derive corresponding temperatures of the decaying cluster ions. The relation between the temperature and the excitation energy (caloric curve) exhibits the typical prerequisites of a first-order phase transition in a finite system, in the present case signaling the transition from a bound cluster to the gas phase.

Event-by-event analysis of collision-induced cluster-ion fragmentation: sequential monomer evaporation versus fission reactions.

The most abundant decay channels have been studied quantitatively for high-energy (60 keV/amu) cluster ions H (3) (+)(H (2))(m = 1-14) colliding with He atoms employing a recently developed multicoincidence technique for the simultaneous detection of the correlated fragments on an event-by-event basis. This allows us to identify decay reactions and their underlying decay mechanisms responsible for the occurrence of the U-shaped fragmentation pattern.

Total, partial, and electron-capture cross sections for ionization of water vapor by 20-150 keV protons.

We present experimental results for proton ionization of water molecules based on a novel event by event analysis of the different ions produced (and lost). We are able to obtain mass analyzed product ion signals (e.g., H2O+, OH+, O+, O++, H+) in coincidence with the projectile analyzed after the collision, i.e., either being H+, neutral H after single electron capture during the ionization event, or H- after double electron capture. After proper calibration we are thus able to determine a complete set of cross sections for the ionization of a molecular target by protons including the total and the partial cross sections and in addition also the direct ionization and the electron capture cross sections.