Kinetics and Thermodynamics of the Reaction between the â¢OH

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Kinetics And Thermodynamics Of The Reaction Between The •OH Radical And Adenine – A Theoretical Investigation Birgitte Olai Milhøj, and Stephan P. A. Sauer J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.5b02711 • Publication Date (Web): 18 May 2015 Downloaded from http://pubs.acs.org on May 23, 2015

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The Journal of Physical Chemistry

Kinetics And Thermodynamics Of The Reaction Between The •OH Radical And Adenine – A Theoretical Investigation Birgitte O. Milhøj∗ and Stephan P. A. Sauer∗ Department of Chemistry, University of Copenhagen, DK-2100 Copenhagen Ø, Denmark E-mail: [email protected]; [email protected]

Phone: 004541108466; 004535320268

∗ To

whom correspondence should be addressed

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Abstract The accessibility of all possible reaction paths for the reaction between the nucleobase adenine and the • OH radical is investigated through quantum chemical calculations of barrier heights and rate constants at the ω B97X-D/6-311++G(2df,2pd) level with Eckart tunneling corrections. First the computational method is validated by considering the hydrogen abstraction from the heterocyclic N9 nitrogen in adenine as a test system. Geometries for all molecules in the reaction are optimised with four different DFT exchange-correlation functionals (B3LYP, BHandHLYP, M062X and ω B97X-D), in combination with Pople and Dunning basis sets, all of which have been employed in similar investigations in the literature. Improved energies are obtained through single point calculations with CCSD(T) and the same basis sets, and reaction rate constants are calculated for all methods both without tunneling corrections and with the Wigner, Bell and Eckart corrections. Compared to CCSD(T)//BHandHLYP/aug-cc-pVTZ reference results, the ω B97XD/6-311++G(2df,2pd) method combined with Eckart tunneling corrections provides a sensible compromise between accuracy and time. Using this method all sub-reactions of the reaction between adenine and the • OH radical are investigated. The total rate constants for hydrogen abstraction and addition for adenine are with this method predicted to be 1.06 ×10−12 cm3 molecules−1 s−1 and 1.10 × 10−12 cm3 molecules−1 s−1 , respectively. Abstractions of H61 and H62 contribute most, while only addition onto the C8 carbon is found to be of any significance contrary to previous claims that addition is the dominant reaction pathway. The overall rate constant for the complete reaction is found to be 2.17 × 10−12 cm3 molecules−1 s−1 , which agrees exceptionally well with experimental results.

Introduction Radiation damage in biomolecules, either by ions or photons, is an active field of research because of its omnipresent implications in modern day life. Not only can improved knowledge of the actual reaction mechanisms involved in radiation damage prove useful in developing protection against 2 ACS Paragon Plus Environment

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said radiation, but it can also lead to an improvement of the current methods of radiation therapy against malignant cells in cancer treatments. Prominent methods of therapeutic radiation include hadron therapy which involve charged particles such as protons or C6+ ion beams aimed selectively at cancer tumours, and exploits the radiation damage to kill the dangerous cancer cells. 1,2 Unfortunately it is impossible to exclusively target and destroy cancer cells, meaning that healthy cells are also being exposed to the radiation resulting in either cell death or further mutation. An increased understanding of the precise reaction mechanism and kinetics, when an ion beam collides with a cell, is needed if one is to increase the effect of ion beam radiation in cancer therapy and thereby minimise the risk of side effects. However, the process is by no means a simple one, 3–5 but consists instead of several separate steps beginning with the interaction of the ion beam radiation with a single molecule in the cell. Statistically the most likely outcome is the reaction with a water molecule, since water exists in excess in all cells. This will potentially result in excitation of the water molecule followed by fragmentation into free • OH, • O and • H radicals in combination with solvated electrons. These highly reactive radicals can then react with other molecules upon collision. One possibility is a reaction between the nucleosides in DNA and the • OH radical and the exact reaction mechanism of this particular type of interaction is the focus of our investigation. Advanced computational calculations of precise barrier heights and reaction rate constants can aid in the understanding of the overall reaction of DNA with the radicals. They can discriminate between possible and impossible reaction paths based on whether the various sub-reactions are thermodynamically favourable and fast enough to be of importance for the overall reaction.

Figure 1: Schematic representation of the investigated hydrogen abstraction reaction from the N9 heterocyclic nitrogen by the • OH radical. In order to reduce the computational cost studying all possible addition and hydrogen abstrac3 ACS Paragon Plus Environment


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tion reactions we wanted to rely solely on density functional theory (DFT). The search for a functional and basis set combination which accurately describe the reactions of the nucleosides in DNA with the • OH radical is therefore the first topic of the present work. The abstraction of hydrogen H9 from the heterocyclic N9 nitrogen in the DNA nucleobase adenine by the • OH radical, as seen in Figure 1, is used as test case for this study, as it has been shown previously that this particular hydrogen carry the largest positive charge of all the hydrogens, making it susceptible for abstraction by the radical. 6 A method and basis set investigation was thus performed, employing DFT methods with energy optimised hybrid functionals, B3LYP 7–9 and BHandHLYP, 10 the hybrid meta-GGA M06-2X, 11 recommended for thermochemical kinetics, and the hybrid ω B97X-D functional, 12 which include long-range interactions and dispersion. All functionals are used in combination with a variety of Pople 13,14 and Dunning 15 basis sets, and rate constants were calculated on the basis of conventional transition state theory, including tunneling effects by means of the Wigner, Bell and Eckart approximations. Reaction energies were, furthermore, improved through CCSD(T) single point calculations utilising the same basis sets. In the subsequent calculations of the rate constants these improved energies were combined with partition functions and frequencies taken from the original pure DFT calculations. In several investigations it was shown that the B3LYP functional tends to underestimate the reaction barrier heights of hydrogen abstraction reactions, which are critical for calculations of accurate rate constants. 16,17 Nevertheless, we have included it in our investigation in order to support or contradict these earlier findings. The relative importance of the different imaginable reactions of the • OH radical with adenine is the topic of the second part of this work. Barrier heights and rate constants are thus calculated for all possible reaction paths with the computational method chosen in the first part. All subreactions needed in the complete reaction picture are investigated, which includes all possible hydrogen abstractions by the • OH radical as well as all • OH additions onto the aromatic carbon atoms in the molecule. The investigated hydrogen abstraction sub-reactions include abstraction of hydrogens from either a carbon or nitrogen site, and it is expected that especially the amine sites are suitable reaction sites due to stronger hydrogen bonds, which makes it easier to reach the


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TS structure. Addition of the • OH radical onto the heterocyclic nitrogens is not investigated as this type of reaction has been shown by Hadad and co-workers to be unimportant for the overall reaction, as they are endoergic and have a much larger activation barrier than the carbon sites. 18 Only a single conformer is found for the intermediates of each reaction, as previous studies have shown that a full conformational search usually affects the rate constants by a factor of less than 10. 19 In the past several theoretical investigations of reactions of the • OH radical with other molecules, be that through hydrogen abstraction or • OH addition, have been performed. Below only the most recent publications are mentioned with a focus on calculations of accurate barrier heights and rate constants. In 2001 Galano et al. looked into hydrogen abstraction reactions from the two amino acids Alanine and Glycine and calculated Eckart corrected rate constants at the PMP2//UMP2/6-311G(2d,2p) level. 20 In 2012 two studies by Castañeda et al. presented Eckart corrected rate constants for reactions of the • OH radical with aldehydes and alkenes through hydrogen abstraction and radical addition calculated at the CCSD(T)//BHandHLYP/6-311++G** level. 21,22 The resulting rate constants were found to agree with experimental values within a factor of two. Ren et al. similarly used CCSD(T)//BHandHLYP/6-311G(d,p) in canonical variational transition-state theory calculations with the small curvature correction on hydrogen abstraction reactions from atmospheric relevant alkyl hydroperoxides and obtained rate constants in equally good agreement with experiments. 23 Rate constants employing the Wigner tunneling correction for reactions with the terephthalate dianion were calculated in 2013 by Tanaka et al. using a variety of functionals good for both longrange interactions and kinetics. 24 Seal et al. validated the use of the M08-HX functional against explicitly correlated CCSD(T)-F12 calculations on the same geometry for the hydrogen abstraction from 1-butanol and calculated accurate temperature dependent rate constants using multi-structural variational transition state theory. 25 Jin et al. used improved canonical variational transition-state theory with the small curvature tunneling correction at the MCG3-MPWB//M06-2X/aug-cc-pVDZ level to calculate rate constants for abstraction reactions from 3-trifluoro-propanole. 26 Scheiner



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benchmarked several DFT methods for the reaction between benzene and the • OH radical against more accurate G3, CBS-QB3 and CCSD(T) calculations and concluded that the M05-2X functional gave the best barrier heights. 27 Another thorough methodology study by Elm et al. on hydrogen abstraction reactions by • OH from several atmospheric relevant molecules conclude that single point improved energies and tunneling corrections are needed for a good description of reaction rates and mechanisms and recommend CCSD(T)-F12/VTZ-F12//BHandHLYP/aug-cc-pVTZ with the Eckart correction. 28 Regarding earlier investigations of reactions between nucleobases and the • OH radical, one should mention the B3LYP calculations of reaction energy profiles for possible hydrogen abstractions from adenine, thymine and cytosine and • OH additions to them. 6,29,30 Another study used both B3LYP and BHandHLYP on cytosine and thymine. 31 For uracil both the B3LYP and MPW1K exchange-correlation functionals were tested against each other in energy calculations with and without CCSD(T) single point energies based on the DFT geometries. 32 Both energies and rate constants for hydrogen abstractions from the sugar moiety 2’-deoxyguanosine using the Wigner correction were investigated at the B3LYP, BHandHLYP and MP2 levels by Shukla et al. 33 To the knowledge of the authors no investigation of the performance of functionals optimised for thermochemical kinetics or including long-range and dispersion corrections have been performed for the reaction of the • OH radical with DNA bases. Based on the previous studies described above we chose in our investigation to use CCSD(T)//BHandHLYP/aug-cc-pVTZ energies in combination with the Eckart tunneling correction as reference for the calculated rate constants, as we expect this method to give very accurate rate constants compared to experiments for both hydrogen abstraction and addition reactions by the • OH radical. Previous experimental studies of the reactions of the • OH-radical with purines at neutral pH by Scholes found a reaction rate constant of 4.3 × 109 M−1 s−1 for adenine, which equals 7.14 × 10−12 cm3 molecules−1 s−1 . 34 The reaction pathway of reactions between various adenine related purine compounds and the • OH

radical was later investigated by Vieira and Steenken and it was suggested that addition is the


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Figure 2: Atom numbering within the adenine molecule. more energetically favourable reaction type, favouring carbon positions C5 and C6 depending on the compound in question, with atom numbering similar to Figure 2. 35–37 Concerning the adenine nucleobase in particular the reaction was found to favour addition of the • OH radical onto C4 with 81%, C8 being second with 18% and a much smaller addition onto C2 of

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