Electron Attachment to Microhydrated Deoxycytidine Monophosphate

Apr 29, 2018 - DNA constituents are effectively decomposed via dissociative electron attachment (DEA). However, the DEA contribution to radiation dama...
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B: Biophysical Chemistry and Biomolecules

Electron Attachment to Microhydrated Deoxycytidine Monophosphate Jaroslav Ko#išek, Barbora Sedmidubská, Suvasthika Indrajith, Michal Fárník, and Juraj Fedor J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.8b03033 • Publication Date (Web): 29 Apr 2018 Downloaded from http://pubs.acs.org on May 1, 2018

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Electron Attachment to Microhydrated Deoxycytidine Monophosphate Jaroslav Kočišek,∗,† Barbora Sedmidubská,‡,† Suvasthika Indrajith,¶ Michal Fárník,† and Juraj Fedor† †J. Heyrovský Institute of Physical Chemistry v.v.i., The Czech Academy of Sciences, Dolejškova 3, 18223 Prague, Czech Republic ‡Deptartment of Nuclear Chemistry, Faculty of Nuclear Sciences and Physical Engineering, Czech Technical University in Prague,Břehová 7,115 19 Prague, CZ. ¶Normandie Univ., ENSICAEN, UNICAEN, CEA, CNRS, CIMAP, 14000 Caen, France E-mail: [email protected]

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Abstract DNA constituents are effectively decomposed via dissociative electron attachment (DEA). However, the DEA contribution to radiation damage in living tissues is a subject of ongoing discussion. We address an essential question, how aqueous environment influences the DEA to DNA. In particular, we report experimental fragmentation patterns for DEA to microhydrated 2-deoxycytidine 5-monophosphate (dCMP). Isolated dCMP was previously set as a model to describe mechanisms of DNA strand breaks induced by secondary electrons and decomposes primarily by dissociation of the C-O phosphoester bond. We show that hydrated molecules decompose via dissociation of the C-N glycosidic bond followed by dissociation of the P-O bond. This significant change of the the proposed mechanism can be interpreted by a reactive role of water in the post-attachment dynamics. Comparison of the fragmentation with previous macroscopic irradiation studies suggests that the actual contribution of DEA to DNA radiation damage in living tissue is rather small.

Introduction DNA damage pathways induced by low energy electrons have attracted an enormous amount of attention during the last decade. This attention is motivated by the efforts to understand the effects of the secondary electrons created when ionizing radiation passes a living tissue. An efficient mechanism that can cause biomolecular decomposition at sub-excitation energies (often even close to 0 eV) is dissociative electron attachment (DEA): AB + e – −−→ A + B – In comparison to neutral dissociation, the dissociation threshold is shifted to lower energies by the electron affinity of the product anion. The assignment of DEA resonances in dry DNA films to the individual DNA components 1,2 and the theoretical rationale for DNA damage by DEA 3,4 have triggered intense investigations of DEA to biomolecules. An overview can

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be found in recent reviews. 5–7 The largest isolated DNA component studied so far with respect to DEA is dCMP. Kopyra 8 identified three main DEA channels of dCMP relevant for single strand breaks in DNA, which resulted in C-O phosphoester bond dissociation with 81% probability (see Fig. 1). In the present study, we show that the water environment completely changes the outcome of the dissociation in favor of the C-N glycosidic bond cleavage. Direct studies of DEA by secondary electrons in water are complicated by fast electron solvation. Early studies combined high-energy irradiation with electron spin resonance spectroscopy. The solvated electrons were shown to interact with DNA bases to form base centered anions. 9,10 Within ns, 11 these anions strip protons from neighboring molecules to form stable dihydrogen base neutral radicals. 12 Therefore, DEA is believed to occur before the electron solvation step. 13,14 Various approaches have been developed to study reactions of secondary electrons before solvation (see e.g. reviews 15–17 ). The main approaches involve i) irradiation of "bulk" films under vacuum, where the energy of electrons can be well controlled but the molecular environment is difficult to control, 16,18,19 and ii) time resolved spectroscopy in solution, with a realistic environment but poor control over the energy of electrons, which can cause contradictory results. 20,21 Here, we prepare individual hydrated biomolecules in vacuum and let them interact with free electrons. We have control over the energy of incident electrons as well as over the environment. 22,23 The complexity of the studied systems is relatively low, which opens a future possibility of a direct comparison with state of the art calculations. The present study may, therefore, not only help to explain the reactivity of electrons in an aqueous environment but also become the benchmark for theory.

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Figure 1: Sketch of the main DEA fragmentation channels of i) the isolated molecule from the previous work of Kopyra 8 and ii) after microhydration from the present study. The isolated molecule i) fragments via three mechanisms. The first, electron attachment directly to the phosphate group resulting in the C-O bond cleavage. The second, direct attachment to the sugar moiety and its complex rearrangement leading to the HCOO− anion. Third, electron attachment to the base and subsequent electron transfer to the C-O sigma antibonding orbital, resulting in the formation of PO− 4 at ∼1 eV. Electron attachment to microhydrated dCMP ii) proceeds via wide bands tentatively assigned to an electron localization on the base. Subsequent intra- or intermolecular proton transfer neutralizes the base reducing the barrier towards C-N bond cleavage. The C5 O6 H9 P(H2 O)− n may further decompose by P-O bond dissociation to form C5 O6 H8 P(H2 O)− . Alternatively, C5 O6 H8 P(H2 O)− n n may be formed by an electron transfer from the base or after direct electron attachment to the sugar moiety.

Methods Configuration of the experiment was identical to the description given in Ref. [22]. Sample molecules were sublimed in a stainless steel oven and mixed with He buffer gas containing a small amount of water. The mixture was expanded through a 90µm conical nozzle into vacuum. The formed molecular beam of microhydrated molecules was crossed with the beam of low energy electrons 1.5 m downstream the nozzle and reaction products were analyzed by the reflectron time-of-flight mass spectrometer. The sample, purchased from Sigma Aldrich, with stated purity ≥95%, was used without further purification. Special attention was given to the sample thermal decomposition. It has been shown that dCMP can be sublimed. 8 However, the temperature needed for a measurable gas phase con-

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centration (398 K) is near to the thermal decomposition point (408 K). 8 We typically used temperatures in the range (398-403) K. The vapor pressure of dCMP, measured by the Leybold CERAVAC CTR91 gauge at 403 K was ∼5x10−5 mbar. After prolonged measurement at ∼403K, we started to see m/z=96 anions in the mass spectrum, which may result from the thermal decomposition of dCMP. In the previous work of Kopyra, 8 the main decomposition product was m/z=97, H2 PO− 4 . The difference can be due low mass resolution of the quadrupole mass spectrometer used in the previous work, which resulted in wrong assignment of the mass or possible dissociation of the neutral precursor within the microhydrated environment in the present study.

Results The fragmentation pattern of microhydrated dCMP following electron attachment is shown in Fig. 2. DEA at low energies (0.5-3.5) eV and high energies (4-13) eV is characterized by cumulative mass spectra in Fig. 2 top and bottom, respectively. The low energy spectrum is dominated by two progressions, C5 O3 H8 (H2 O)− n cluster anions starting with n=0 at m/z=116 and C5 O6 H9 P(H2 O)− n cluster anions starting with n=0 at m/z=196. The first, dominant progression is formed by dissociation of the glycosidic C-N and the sugar-phosphate P-O bonds. The second progression is formed by dissociation of the C-N bond and one H atom abstraction from the resulting anion. Clearly, DEA to microhydrated dCMP below ∼3 eV is dominated by the glycosidic bond cleavage. Ion yields for particular ions as a function of the incident electron energy are shown at the top of Fig. 3. Both dominant anion progressions are formed as broad bands spanning up to 2.5 eV, which can be assigned to electron attachment by the base. The large width of the observed bands in comparison to the experiments with isolated cytosine 24 can be caused by the width of the electron energy distribution function in the present experiment (see 25 for

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Figure 2: Cumulative negative ion mass spectra for electron energies (0.5-3.5) eV (top panel) and (4-13) eV (bottom panel). The spectra were obtained as a sum of mass spectra measured in the given energy range with the step of 0.25 eV and 1 eV, respectively. details) but it can have also a physical reason. Nucleotides can have different positions of resonances in comparison with free bases. 26 The surrounding water may also contribute to the width of the observed bands. 27–29 − Other detected fragments are PO− 4 and PO2 anions formed with low intensities close to

∼0 eV and a (H2 O)n OH− progression. Water clusters may form a background in the molecular beam. However, at low energies, electron attachment to water clusters leads to intact 30 (H2 O)− This indicates that the progression origin anions, DEA occurs only above ∼6 eV.

nates from DEA to complexes of dCMP with water. We have observed similar behavior for complexes of NO with water. 31 The bottom panel of Fig. 2 shows the fragmentation pattern at higher electron energies (4-13) eV. DEA to microhydrated dCMP at these energies is inefficient. There are two

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followed by much weaker signal of its hydrated cluster anions C5 O3 H7 (H2 O)− n . Their corresponding energy dependent ion yields are at the bottom of Fig. 3. The H2 PO− 4 anion peaks at the lowest energy ∼6 eV, followed by water clusters at ∼6.5 eV and C5 O3 H7 (H2 O)− n at ∼8 eV.

Discussion The dominant cleavage of the C-N and P-O bonds by low energy electrons observed in the present study is in strong contrast to previous experimental as well as theoretical studies. The primary site of electron induced damage was always assigned to the C-O phosphoester bond. This was based on the results of experiments with the isolated molecules 8 as well as with dry dCMP samples on a surface. 32 Rupture of the C-O bond was also directly linked to single strand breaks in DNA by theory (see e.g. reviews 33,34 ) Calculated barriers for the C-O bond dissociation after electron attachment were always lower than for the C-N bonds. 7

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− We observe PO− 4 and PO2 anions resulting from this channel. However, their intensities are

almost negligible. Suppression of this channel after hydration may stem from a screening effect. The anions are observed near 0 eV (Fig. 3). Based on previous experiments 8 and theoretical predictions, 35 these anions may be formed by direct electron attachment to the phosphate. However, the energies of unoccupied orbitals of the PO4 group are high. 36,37 One option is that gas-phase dissociation near 0 eV is mediated by dipole-bound or virtual states. 38 We have recently shown that their formation can be effectively suppressed by electrostatic shielding caused by the environment. 39,40 The presence of water may thus suppress the attachment to phosphate and consequently the probability for C-O bond cleavage. Similar suppression of low energy DEA resonances by environment was observed in the the recent experiments with Bromoadenine modified DNA segments on DNA origami templates. 41 On the other hand, such suppression was not observed in experiments with dry DNA films. 42 We demonstrate that after hydration, the most probable DEA channel results in C-N bond dissociation. Such behavior can not be explained on the basis of calculations treating water as a polarized continuum. 4,34,43,44 However, it can be explained by a fast proton transfer and base neutralization. In DNA, such transfer was proposed to occur from a neighboring base, 45,46 which is not possible in our experiments. More recently, for slightly different system of 2-deoxycytidine 3-monophosphate, 47 the proton transfer from the neighboring water molecules has been proposed. After such base neutralization, the C-N bond dissociates with higher probability than the C-O bond, in accord with the present observation. Formation of the C5 O3 H8 (H2 O)− n anions requires a cleavage of the P-O sugar phosphate bond. The P-O bond is the weakest in the DNA backbone and undergoes dramatic prolongation after electron attachment in water environment. 48 Despite of that, P-O bond cleavage is typically observed with a low relative abundance. 49–51 It has been proposed by Rak et al. 52 that such cleavage proceeds via a hydrogen transfer from sugar to the monohydroradical of base (dihydrogen base radical formation step) within a nucleotide neutral formed by protonation of the nucleotide anion. The sugar phosphate part is then unstable towards the

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Figure 4: Relative intensities of individual peaks in the progression of hydrated anion frag− ments C5 O3 H8 (H2 O)− n and C5 O6 H9 P(H2 O)n , which demonstrate decrease of the intensity − after n=1 and n=4 C5 O3 H8 (H2 O)n cluster anions in contrast to rather smooth hydration of C5 O6 H9 P− anion. P-O bond breakage. Our observation of fully hydrogenated sugar anions resulting from such breakage, indicates that the similar mechanism may occur in anion state, but hydrogen in not transferred from the sugar. The hydrogen may be transferred from the neighboring water, or from the phosphate (see schematics in Fig. 1). The latter explanation is supported by the fact that C5 O6 H9 P(H2 O)− n anions have one hydrogen less than their expected neutral precursors. However, solely on the basis of our experimental data, we cannot exclude the possibility that the phosphate is deprotonated prior to the electron attachment due to solvation. With respect to the proposed mechanisms, it is interesting to explore the stability of the formed cluster anions shown in Fig. 4. While the distribution of water molecules in the − C5 O6 H9 P(H2 O)− n clusters shows a rather smooth dependence on n, in the C5 O6 H8 P(H2 O)n

case, we observe drops in the intensity after n=1 and n=4. Assuming an evaporative ensemble fragmentation, these steps indicate particular stability for the n=1 and n=4 structures. It is worth mentioning that C5 O3 H− 8 may be actually formed by direct electron attachment to the sugar moiety. Calculations of electron distributions in DNA segments after electron attachment show that sugar is always positively charged. 34,45 However, the gas phase electron affinity of C5 O3 H8 of ∼2 eV (present 53 B3LYP-D3/aug-cc-pVDZ value) is enough to support the present observation of sugar containing anions. In the experiments with isolated 9

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dCMP, 8 the formation of HCOO− anions was assigned to direct electron attachment to the sugar moiety. P-O bond fragmentation analogous to our observation was then reported in the study of d-ribose-5-phosphate. 54 Effective damage induced by low energy electrons to the sugar part of plasmid DNA was observed also by Chen et al. 55 The cross sections for electron attachment to ribose 56 are orders of magnitude larger than that to DNA bases. 57,58 Even though the attachment cross section may vary with the number of OH groups attached to the sugar moiety, 59 this channel should not be overlooked. The recent picosecond transient absorption study 21 shows that nucleobase anions effectively stabilize in solution, in complete agreement with our previous studies of microhydrated DNA bases 22 and theoretical predictions. 60 However, the same study shows that whole nucleotide transient anions could be stabilized by the environment. We have no evidence for this behavior in our experiment. This might be caused by the low relative abundance of DEA in the bulk water, as discussed in the following paragraph. The most intense C5 O3 H8 (H2 O)− n anion progression observed in the present study results from the cleavage of the P-O bond. Radicals resulting from the P-O bond dissociation were assigned to DEA also in previous studies of DNA in bulk water 49 and dry films of DNA segments. 50,51 However, in the ESR study of Becker et al., 49 these radicals were observed only with low intensities of ∼0.1%. In our experiments, we are not able to detect neutral radical species from DEA process. The studied microhydrated dCMP also do not have character of dCMP in bulk water. However, we observe fragmentation change from dry to microhydrated conditions resulting from C-O bond to P-O bond cleavage. If we assume the same change occurring when moving from dry DNA films to DNA in solution and set the P-O bond dissociation as a primary DEA process in water, the radicals observed in the work of Becker et al. may be a fingerprint of DEA in radiation chemistry. Their low abundance then indicates rather low importance of the DEA-induced damage to DNA by secondary electrons.

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Conclusions In the present study, we probe the fragmentation of microhydrated dCMP by low energy electrons in the (0.5-13) eV range. Isolated dCMP was set as a model for molecular mechanism of electron induced DNA strand breaks. 8 In contrast to isolated molecules, we observe glycosidic C-N and sugar-phosphate P-O bond dissociations as the primary and secondary fragmentation channels, respectively. Sugar containing anions dominate the observed mass spectrum in contrast to the phosphate and base radical anions typical for dry conditions. This observation may be partially described on the basis of previous theoretical predictions including fast proton and hydrogen transfer after DEA. 45,52,61 Comparison with the decomposition pattern of the solvated DNA 49 suggests that DEA is responsible only for a small degree of the damage induced by radiation.

Acknowledgement The present work has been supported by the Czech Science Foundation grant number 1610995Y. JK and SI acknowledge the support of Czech Ministry of Youth, Sports and Education mobility program Barrande, project 7AMB17FR047.

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(11) Visscher, K.; Haas, M. D.; Loman, H.; Vojnovic, B.; Warman, J. Fast Protonation of Adenosine and of Its Radical Anion Formed by Hydrated Electron Attack; A Nanosecond Optical and Dc-Conductivity Pulse Radiolysis Study. International Journal of Radiation Biology and Related Studies in Physics, Chemistry and Medicine 1987, 52, 745–753. (12) Novais, H. M.; Steenken, S. ESR Studies of Electron and Hydrogen Adducts of Thymine and Uracil and Their Derivatives and of 4,6-Dihydroxypyrimidines in Aqueous Solution. Comparison with Data from Solid State. The Protonation at Carbon of the Electron Adducts. Journal of the American Chemical Society 1986, 108, 1–6. (13) Sanche, L. Beyond Radical Thinking. Nature 2009, 461, 358–359. (14) Sevilla, M. D.; Becker, D.; Kumar, A.; Adhikary, A. Gamma and Ion-Beam Irradiation of DNA: Free Radical Mechanisms, Electron Effects, and Radiation Chemical Track Structure. Radiation Physics and Chemistry 2016, 128, 60 – 74. (15) Alizadeh, E.; Sanche, L. Precursors of Solvated Electrons in Radiobiological Physics and Chemistry. Chemical Reviews 2012, 112, 5578–5602. (16) Alizadeh, E.; Orlando, T. M.; Sanche, L. Biomolecular Damage Induced by Ionizing Radiation: The Direct and Indirect Effects of Low-Energy Electrons on DNA. Annual Reviews of Physical Chemistry 2015, 66, 379–398. (17) Rezaee, M.; Hill, R. P.; Jaffray, D. A. The Exploitation of Low-Energy Electrons in Cancer Treatment. Radiation Research 2017, 188, 123–143. (18) Purkayastha, S.; Milligan, J. R.; Bernhard, W. A. Correlation of Free Radical Yields with Strand Break Yields Produced in Plasmid DNA by the Direct Effect of Ionizing Radiation. The Journal of Physical Chemistry B 2005, 109, 16967–16973.

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(27) Sieradzka, A.; Gorfinkiel, J. D. Theoretical Study of Resonance Formation in Microhydrated Molecules. II. Thymine-(H2O)n, n = 1,2,3,5. The Journal of Chemical Physics 2017, 147, 034303. (28) Sieradzka, A.; Gorfinkiel, J. D. Theoretical Study of Resonance Formation in Microhydrated Molecules. I. Pyridine-(H2O)n, n = 1,2,3,5. The Journal of Chemical Physics 2017, 147, 034302. (29) de Oliveira, E. M.; Freitas, T. C.; Coutinho, K.; Varella, M. T. N.; Canuto, S.; Lima, M. A. P.; Bettega, M. H. F. Communication: Transient Anion States of Phenol...(H2O)n (n = 1, 2) Complexes: Search for Microsolvation Signatures. The Journal of Chemical Physics 2014, 141, 051105. (30) Fedor, J.; Cicman, P.; Coupier, B.; Feil, S.; Winkler, M.; Głuch, K.; Husarik, J.; Jaksch, D.; Farizon, B.; Mason, N. J. et al. Fragmentation of Transient Water Anions Following Low-Energy Electron Capture by H 2 O/D 2 O. Journal of Physics B: Atomic, Molecular and Optical Physics 2006, 39, 3935. (31) Šmídová, D.; Lengyel, J.; Kočišek, J.; Pysanenko, A.; Fárník, M. Analysis of Mixed Nitric Oxide-Water Clusters by Complementary Ionization Methods. International Journal of Mass Spectrometry 2017, 421, 144 – 149. (32) Krilov, D.; Herak, J. ESR Evidence For the Radiation-Induced Breakage of the Sugar-Phosphate Bonds in Nucleotides:

Single Crystal of Deoxycytidine 5âĂš-

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(34) Kumar, A.; Sevilla, M. D. In Handbook of Computational Chemistry; Leszczynski, J., Ed.; Springer Netherlands: Dordrecht, 2016; pp 1–63. (35) Li, X.; Sevilla, M. D.; Sanche, L. Density Functional Theory Studies of Electron Interaction with DNA: Can Zero eV Electrons Induce Strand Breaks? Journal of the American Chemical Society 2003, 125, 13668–13669. (36) Berdys, J.; Anusiewicz, I.; Skurski, P.; Simons, J. Damage to Model DNA Fragments from Very Low-Energy (