Mechanisms Responsible for High Energy Radiation Induced Damage

Article pubs.acs.org/JPCB

Mechanisms Responsible for High Energy Radiation Induced Damage to Single-Stranded DNA Modified by Radiosensitizing 5‑Halogenated Deoxyuridines Shoushan Wang, Peiwen Zhao, Changzhe Zhang, and Yuxiang Bu* School of Chemistry and Chemical Engineering, Institute of Theoretical Chemistry, Shandong University, Jinan 250100, P. R. China S Supporting Information *

ABSTRACT: Experimental studies showed that high energy radiation induced base release and DNA backbone breaks mainly occur at the neighboring 5′ nucleotide when a single-stranded DNA is modified by radiosensitizing 5-halogenated deoxyuridines. However, no mechanism can be used to interpret these experimental observations. To better understand the radiosensitivity of 5-halogenated deoxyuridines, mechanisms involving hydrogen abstraction by the uracil-5-yl radical from the C2′ and C3′ positions of an adjacent nucleotide separately followed by the C3′−O3′ or N−glycosidic bond rupture and the P−O3′ bond breakage are investigated in the DNA sequence 5′-TU•-3′ employing density functional theory calculations in the present study. It is found that hydrogen abstractions from both positions are comparable with the one from the C2′ site slightly more favorable. The N−glycosidic bond cleavage in the neighboring 5′ nucleotide following the internucleotide C2′−Ha abstraction is estimated to have the lowest activation free energies, indicating that the adjacent 5′ base release dominates electron induced damage to single-stranded DNA incorporated by 5-halogenated deoxyuridines. Relative to the P−O3′ bond breakage after the internucleotide C3′-H abstraction, the C3′−O3′ bond rupture in the neighboring 5′ nucleotide following the internucleotide C2′-Ha abstraction is predicted to have a lower activation free energy, implying that single-stranded DNA backbone breaks are prone to occur at the C3′−O3′ bond site. The 5′-TU•-3′ species has substantial electron affinity and can even capture a hydrated electron, forming the 5′-TU−-3′ anion. However, the electron induced C3′−O3′ bond rupture in 5′-TU−-3′ anion via a pathway of internucleotide proton abstraction is only minor in both the gas phase and aqueous solution. The present theoretical predictions can interpret rationally experimental observations, thereby demonstrating that the mechanisms proposed here are responsible for high energy radiation induced damage to single-stranded DNA incorporated by radiosensitizing 5-halogenated deoxyuridines. By comparing with previous results, our work proves that the radiosensitizing action of 5-bromo-2-deoxyuridine is not weaker but stronger than its isomer 6-bromo-2-deoxyuridine on the basis of the available data.

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INTRODUCTION Radiotherapy is one of the three most commonly used treatments to human cancers (besides chemotherapy and photodynamic therapy).1 DNA is confirmed experimentally to be the primary target for anticancer radiotherapy.2 Thus, DNA damage induced by high energy radiations is related to cancer cell apoptotic death. Large amounts of hydrogen atoms (H•), hydroxyl radicals (OH•), and low energy electrons with electron energies mainly below 20 eV are created along all the ionizing radiation tracks.3 These radiolysis products of water are considered to be involved in DNA damage mechanisms. The oxidizing OH• (reducing H•) radical addition and abstraction to various DNA components were once believed to be the primary pathways leading to DNA lesions.4,5 However, efficient DNA single- and double-stranded breaks induced by prehydrated electrons (the precursors of hydrated electrons) were detected with the damage effectiveness per prehydrated electron nearly twice than that per OH• radical.6,7 On the other hand, it was found that oxic cells are 2.5−3 times more susceptible to high energy radiations than hypoxic cells.8 © XXXX American Chemical Society

Unfortunately, cancer cells are always in the hypoxic conditions.9 Therefore, to reduce the therapeutic dose and the occurrence of possible side effects,10,11 the introduction of radiosensitizers, which can be readily incorporated into DNA sequence without changing normal gene expressions, have a deeper potential well than regular DNA bases to capture a thermal or even hydrated electron, and can be easily degradated into highly reactive species upon electron attachment, is required for efficient anticancer radiotherapy. 5-Halogenated deoxyuridines (denoted as 5XdU, especially the 5BrdU and 5IdU) are a class of radiosensitizers satisfying the above-mentioned requirements. The radiosensitivity of 5XdU has been extensively investigated in different DNA fragments12−18 and cancer cells.19−22 Impressive single- and double-stranded breaks,12−14 intra- and interstrand crosslinks,15−17 alkali-labile lesions,14 chromosomal aberrations,19 Received: November 23, 2015 Revised: February 21, 2016

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DOI: 10.1021/acs.jpcb.5b11432 J. Phys. Chem. B XXXX, XXX, XXX−XXX

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The Journal of Physical Chemistry B and base releases18 were detected. Moreover, the potential anticancer applications of 5XdU were further demonstrated in clinical trials.23−28 The radiosensitizing character of 5XdU is attributed to their considerable electron affinities having enough ability to bind a radiation-produced secondary electron.29,30 The estimated electron affinities of 5-halogenated uracil derivatives lie in a range 0.37−0.64 eV in the gas phase and 2.21−2.60 eV in aqueous solution,31−34 which are separately much higher than those of native nucleobase derivatives (−0.37 to 0.44 eV in the gas phase and 0.95 to 2.18 eV in aqueous solution).35,36 Experimental studies showed that the anions formed by 5-halogenated uracil derivatives interacting with secondary electrons are only metastable intermediates, which can go through a rapid halide anion elimination reaction producing the uracil-5-yl radical.36−42 Theoretical calculations31−34,43 and simulations44,45 predicted that the halide anion elimination process is spontaneous or needs surmounting only a small kinetic barrier in both the gas phase and aqueous solution, demonstrating the experimental observations. The produced uracil-5-yl radical is highly reactive, thereby being considered to be able to attack surrounding molecular fragments (such as the 2′-deoxyribose moiety of the same or an adjacent nucleotide) or molecules leading to diverse DNA lesions. Possible electron induced P−O bond breakages in 5-bromo2′-deoxyuridine 3′,5′-diphosphates (5-BrdUDP) leading to DNA backbone breaks when being incorporated into DNA sequence were investigated.34 After eliminating the bromide anion, P−O3′ and P−O5′ bond ruptures starting from the debrominated 5-*dUDP radical via a mechanism of intranucleotide hydrogen transfer separately from the C3′ and C5′ atoms to the C5 site were estimated. The calculated free energy barriers for the intranucleotide hydrogen transfer step are no less than 43.92 kcal/mol, indicating that neither bond rupture is possible. Steric hindrance from the C6 atom and its bonded hydrogen atom is responsible for these exceptionally high energy requirements. In addition, it should be noted that the dominant electron induced bond rupture site leading to DNA backbone breaks is the C3′−O3′ bond rather than the two P−O bonds, as determined in T5BrUT trimeric oligonucleotide experiments.18,46 Hence, the damage mechanisms of DNA modified by 5BrdU or 5IdU under the stimulus of high energy radiations are still unclear, and further studies are needed to better understand the radiosensitivity of 5XdU. Hydrogen abstractions by the uracil-5-yl radical from the C1′ and C2′ positions of a neighboring nucleotide in the DNA sequence 5′-AU•-3′ have been studied.47 The calculated results demonstrated the feasibility of both hydrogen abstraction pathways with the one from C1′ position more favorable when the nearby adenine remains neutral. However, one thing should be noted that the basis set used there (3-21G*) is relatively coarse. After hydrogen abstraction from the C2′ position, the spin density center is transferred to the C2′ site of the neighboring 2′-deoxyribose moiety, making the nearby C3′−O3′ and N−glycosidic bond ruptures possible. Such bond breakages, which have not been studied up to now to our best knowledge, may be involved in radiation induced damage to DNA modified by 5XdU. On the other hand, hydrogen abstraction from the C3′ site was predicted to be feasible in radiosensitizing studies of 6-bromo-2-deoxyuridine 3′,5′diphosphate,34 6-bromo-2-deoxycytidine 3′,5′-diphosphate,1 8bromo-2′-deoxyadenosine 3′,5′-diphosphate,29 and 8-bromo2′-deoxyguanine 3′,5′-diphosphate.30 Similarly, the uracil-5-yl

radical may abstract the hydrogen atom located at the C3′ position of a neighboring nucleotide leading to subsequent P− O3′ bond cleavage. Besides effectively eliminating the halide anion, the gas phase experimental studies showed that 5-halouracil can also eliminate a halide atom leaving the uracil-5-yl anion upon secondary electron attachment.37 On the other hand, the socalled “spurs” of low energy electrons can be created near the modified DNA in radiated aqueous solution.48 It is possible for the electron-deficient uracil-5-yl radial to capture an excess electron, forming the corresponding uracil-5-yl anion. Previous theoretical studies demonstrated that deprotonation of the C2′ site is accompanied by the nearby C3′−O3′ bond rupture.49,50 Thus, electron attachment to the dehalogenated uracil-5-yl radical followed by internucleotide proton abstraction from the neighboring C2′ site may be another pathway leading to DNA single-stranded breaks. In the present work, the mechanisms in which hydrogen abstraction by the uracil-5-yl radical from the C2′ and C3′ sites of a neighboring 2′-deoxyribose moiety separately followed by the C3′−O3′ or N1−C1′ bond rupture and the P−O3′ bond cleavage in the DNA sequence 5′-TU•-3′ are explored. In addition, electron attachment to the DNA sequence 5′-TU•-3′ and subsequent possible C3′ −O 3′ bond rupture via a mechanism of internucleotide proton transfer are also studied. It is found that both hydrogen abstraction pathways are comparable with the one from the C2′ site slightly more preferable. The species 5′-TU•-3′ is predicted to be able to capture a hydrated electron due to its significantly large electron affinity. Activation free energy calculations indicate that the adjacent 5′ base release from the N−glycosidic bond cleavage is the most probable electron induced damage when 5BrdU or 5IdU is incorporated into a single-stranded DNA. Instead of the P−O3′ bond, single-stranded DNA backbone breaks are prone to occur at the C3′−O3′ bond via a mechanism of internucleotide hydrogen abstraction rather than internucleotide proton transfer. All predictions are well consistent with experimental observations, demonstrating the rationality of the proposed mechanisms.

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COMPUTATIONAL DETAILS All geometry optimizations and single-point energy calculations were carried out at the B3LYP51,52 level in conjunction with a 6-31+G(d,p) basis set. The B3LYP/6-31+G(d,p) method has been verified to be reliable for the DNA-related systems in previous studies.53−56 Frequency analyses were performed to assess the nature of stationary points on the potential energy surfaces. All transition states were subject to intrinsic reaction coordinate (IRC) calculations to confirm the connection between the reactants and products. To take into account the solvent effects, the polarizable continuum model (PCM)57 with ε = 78.39 was employed. Related energy changes in each reaction process were estimated on the basis of Gibbs free energies calculated in the rigid-rotor harmonic oscillator approximation at T = 298 K and p = 1 atm. Solvation free energies were considered when calculating solvated systems. A sequence 5′-TT-3′ extracted from an experimental X-ray crystal structure of a B-DNA (PDB code: 3BSE) was used to construct the sequence 5′-TU•-3′ by removing the relevant methyl group. The phosphate group in the sequence 5′-TU•-3′ was further protonated to mimic the physiological conditions in which a counterion such as Na+ or K+ exists in the vicinity of the B


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Figure 1. Optimized structures for stationary points along the C2′−Ha abstraction process by the neighboring uracil-5-yl radical in the sequence 5′TU•-3′. Distances are in Å.

Figure 2. Optimized structures for stationary points along the C3′−H abstraction process by the neighboring uracil-5-yl radical in the sequence 5′TU•-3′. Distances are in Å.

Table 1. Kinetic (ΔE* and ΔG*) and Thermodynamic (ΔE and ΔG) Characteristics of Hydrogen Abstractions by the Uracil-5yl Radical Separately from the Neighboring C2′ and C3′ Positions (Energies Are in kcal/mol) C2′-Ha abstraction vacuum solution

C3′-H abstraction

ΔE*

ΔG*

ΔE

ΔG

ΔE*

ΔG*

ΔE

ΔG

5.39

6.66 3.97

−20.39

−20.01 −19.54

6.72

8.12 4.92

−23.30

−23.46 −24.39

phosphate group, as in other similar studies.58−62 All calculations were carried out using the Gaussian 03 package.63

for hydrogen abstraction from the C2′ position (denoted as TS1, verified by having only one imaginary frequency 1381.88i cm−1 and the IRC calculations), the transferred C2′−Ha atom is 1.26 Å away from the C2′ atom and 1.45 Å to the C5 atom (Figure 1). The C2′−C1′ and C2′−C3′ bond lengths are reduced from 1.54 and 1.53 Å in the reactant 5′-TU•-3′ to 1.53 and 1.52 Å at the TS1 state and further decreased to be 1.50 and 1.48 Å in the hydrogen transferred product (denoted as 5′-•TC2′U-3′, the subscript represents the site from which hydrogen is abstracted, Figure 1). The alteration of the C2′ hybridization in the hydrogen transfer process is responsible for these bond length variations. The sum of the three related angles, ∠C1′C2′C3′ + ∠C1′C2′Hb + ∠C3′C2′Hb, changes from 327.6° in 5′-TU•-3′ to 359.1° in 5′-•TC2′U-3′ via a value of 333.4° at the TS1 state, indicating that the C2′ hybridization is transformed from sp3 in the reactant 5′-TU•-3′ to sp2 in the product 5′-•TC2′U-3′. In general, the C−C bond lengths associated with sp2 hybridization are shorter than those associated with sp3 hybridization. The kinetic barrier and activation free energy for this internucleotide hydrogen abstraction are estimated to be 5.39 and 6.66 kcal/mol, respectively (Table 1). Our calculated activation energy (5.39 kcal/mol) is much smaller than that of hydrogen abstraction by the uracil-5-yl radical from the C2′ position of a neighboring deoxyadenine (11.17 kcal/mol).47 The reasons for this may be attributed to the use of different base sequences (5′-AU•-3′ vs 5′-TU•-3′)64 and the relatively

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RESULTS AND DISCUSSION Since the mechanism of halide anion elimination has been clarified definitely,31−34,44 the current work thus neglects this process and focuses primarily on possible bond ruptures following hydrogen abstractions by the uracil-5-yl radical or proton abstraction by the uracil-5-yl anion. It is clear that there is no steric hindrance between the spin density center, the C5 atom, of the uracil-5-yl radical and the hydrogen atoms bonded to C2′ and C3′ atoms of the neighboring 2′-deoxyribose moiety in the optimized 5′-TU•-3′ sequence (Figures 1 and 2). Moreover, the distances from the C5 atom of the uracil-5-yl radical to the C2′−Ha, C2′−Hb, and C3′−H atoms are moderate, only 2.75, 4.28, and 2.91 Å, respectively. Accordingly, hydrogen abstractions from both the neighboring C2′ and C3′ positions are probable. However, it should be noted that the C2′−Hb bond direction is nearly antiparallel to the plane of the adjacent uracil moiety, making the C2′−Hb abstraction unfavorable relative to that of C2′−Ha (Figure 1). Thus, only the C2′−Ha and C3′−H atoms are taken into account for internucleotide hydrogen abstractions by the uracil-5-yl radical. As described in the Introduction, only the C2′ protons are considered herein for the internucleotide proton abstraction. Hydrogen Abstraction by the Uracil-5-yl Radical from the Neighboring C2′ Position. At the located transition state C


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Figure 3. C3′−O3′ bond rupture pathway: stationary structures with selected geometric parameters. Distances are in Å.

Figure 4. N1−C1′ bond cleavage pathway: stationary structures with selected geometric parameters. Distances are in Å.

in 5′-TU•-3′ to 1.53, 1.54, and 1.43 Å at the TS2 state and eventually to 1.50, 1.51, and 1.40 Å in 5′-•TC3′U-3′ (Figure 2). The calculated gas phase and aqueous phase activation free energies for the C3′-H atom transfer process are 8.12 and 4.92 kcal/mol, respectively (Table 1). These energy requirements are comparable to those corresponding values for hydrogen abstraction from the neighboring C2′ site but also significantly lower than those for intranucleotide hydrogen abstractions separately from the C3′ and C5′ positions in the 5-*dUDP radical.34 The C3′-H abstraction reaction is thermodynamically favorable with the free energy released being 23.46 kcal/mol in the gas phase and 24.39 kcal/mol in aqueous solution (Table 1). Thus, besides the adjacent C2′ position, the neighboring C3′ position is also one of the most probable sites for hydrogen abstraction by the formed uracil-5-yl radical in a single-stranded DNA modified by 5BrdU or 5IdU. Possible Bond Ruptures Following Hydrogen Abstraction from the Neighboring C2′ Site. After C2′-Ha abstraction, the spin density center is transferred from the original C5 atom in 5′-TU•-3′ to the neighboring C2′ site in 5′-•TC2′U-3′. This unpaired electron distribution in 5′-•TC2′U3′ may make the nearby C3′−O3′ or N1−C1′ bond homolytic cleavage forming the C2′C3′ or C2′C1′ double bond. The related stationary points along the C3′−O3′ and N1−glycosidic bond cleavage pathways are depicted in Figures 3 and 4, respectively. At the transition state of the C3′−O3′ bond rupture (denoted as TS3, verified by having only one imaginary frequency 104.35i cm−1 and the IRC calculations), the C3′−O3′ bond distance is elongated to 2.26 Å from a value of 1.47 Å in the reactant 5′-•TC2′U-3′ (Figure 3). Meanwhile, the adjacent C2′−C3′ bond length shrinks from 1.48 to 1.37 Å. The C3′−O3′ bond rupture product is a complex stabilized by two hydrogen bonds, and the C2′−C3′ bond length is now decreased to be 1.33 Å (a representative CC double bond) with other bonds remaining nearly unchanged (Figure 3). The activation free energy for the C3′−O3′ bond rupture is calculated to be 17.19 kcal/mol in the gas phase and 17.36

coarse basis set (3-21G*) employed in the previous study.47 The C2′-Ha transfer reaction is exothermal with the reaction energy and free energy being −20.39 and −20.01 kcal/mol, respectively (Table 1). Thus, hydrogen abstraction by the uracil-5-yl radical from the C2′ position of a neighboring 2′deoxyribose moiety is not only kinetically but also thermodynamically favorable. The activation free energy for the C2′-Ha abstraction is slightly decreased (3.97 kcal/mol, Table 1) when the polarizable environment is taken into account. Notably, this value is significantly lower than those (43.92−75.53 kcal/mol) for intranucleotide hydrogen abstractions separately from the C3′ and C5′ sites in the 5-*dUDP radical,34 demonstrating that internucleotide hydrogen abstraction is kinetically more favorable than intranucleotide hydrogen abstraction for the uracil-5-yl radical. The aqueous phase C2′-Ha transfer reaction is also exothermal with the reaction free energy being −19.54 kcal/mol (Table 1). Thus, after electron attachment induced elimination of the halide anion, the neighboring C2′ position is one of the most probable sites for hydrogen abstraction by the produced uracil-5-yl radical in a single-stranded DNA incorporated by 5BrdU or 5IdU. Hydrogen Abstraction by the Uracil-5-yl Radical from the Neighboring C3′ Position. The transferred C3′-H atom is 1.23 Å away from the C3′ site and 1.48 Å to the C5 atom at the transition state of hydrogen abstraction from the C3′ position (denoted as TS2, verified by having only one imaginary frequency 1007.18i cm−1 and the IRC calculations, Figure 2). The hydrogen loss from the C3′ atom weakens its sp3 hybridization with a tendency of being transformed to sp2 hybridization, as reflected by the change of the sum of three relevant angles ∠C2′C3′C4′ + ∠C2′C3′O3′ + ∠C4′C3′O3′ (from 326.2° in the reactant 5′-TU•-3′ to 345.4° in the hydrogen transferred product 5′-•TC3′U-3′ via a value of 333.5° in the TS2 state). Therefore, the related C2′−C3′, C3′−C4′, and C3′− O3′ bond lengths shrink separately from 1.53, 1.55, and 1.46 Å D


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Table 2. Kinetic (ΔG*) and Thermodynamic (ΔG) Characteristics of Possible Bond Breakages after Hydrogen Abstractions from the Neighboring C2′ and C3′ Sites (Energies Are in kcal/mol) C3′−O3′ bond rupture vacuum solution

N1−C1′ bond rupture

P−O3′ bond rupture

ΔG*

ΔGa

ΔGtb

ΔG*

ΔGa

ΔGtb

ΔG*

ΔGa

ΔGtb

17.19 17.36

4.15 2.49

−13.63 −13.30

15.49 14.49

−0.92 −0.94

−18.71 −16.74

19.47 19.87

1.63 3.82

−19.61 −16.83

ΔG represents the reaction free energy only for the relevant bond rupture reaction step. bΔGt represents the total reaction free energy calculated from the sequence 5′-TU•-3′. a

Figure 5. P−O3′ bond breakage pathway: stationary structures with selected geometric parameters. Distances are in Å.

kcal/mol in aqueous solution (Table 2), implying that the C3′− O3′ bond rupture is kinetically feasible. Although the reaction free energy for the C3′−O3′ bond rupture is estimated to be positive (2.49−4.15 kcal/mol endothermic), the total reaction free energy including the C2′−Ha abstraction step is much negative (−13.63 kcal/mol in the gas phase and −13.30 kcal/ mol in aqueous solution, Table 2), indicating that the total reaction process starting from the sequence 5′-TU•-3′ is thermodynamically favorable. Experimental studies on low energy electron bombarded T5BrUT oligonucleotides65 and irradiated T5BrUT aqueous solution showed that DNA backbone breaks mainly occur at the C3′−O3′ bond of the adjacent 5′ thymine nucleotide.46 Clearly, the mechanism determined here, hydrogen abstraction by the formed uracil-5yl radical from the neighboring C2′ site followed by the C3′−O3′ bond rupture in the adjacent 5′ nucleotide, can reasonably interpret these experimental observations. Besides the C3′−O3′ bond, the homolytic cleavage of the N1−C1′ bond leading to the neighboring 5′ base release is also investigated. The N1-glycosidic bond is elongated from 1.46 Å in the reactant 5′-•TC2′U-3′ to 2.10 Å at the transition state (denoted as TS4, verified by having only one imaginary frequency 347.77i cm−1 and IRC calculations, Figure 4). Correspondingly, the C1′−C2′ bond length is shortened from 1.50 to 1.40 Å. The N1−C1′ bond cleavage product Pro2 is a complex stabilized by a weak hydrogen bond, and the C1′−C2′ bond length is further reduced to be 1.34 Å (a representative CC double bond) in the abasic nucleotide making the 2′deoxyribose moiety planar. Changes of other bond lengths are insignificant along the N1−C1′ bond cleavage process (Figure 4). The estimated gas phase and aqueous phase activation free energies for the N1−C1′ bond rupture are 15.49 and 14.49 kcal/ mol, respectively. These free energy requirements are 1.70− 2.87 kcal/mol lower than those for the C3′−O3′ bond breakage (Table 2). In contrast to the case of C3′−O3′ bond rupture, the N1−C1′ bond cleavage process is exothermal in both the gas phase (0.92 kcal/mol) and aqueous solution (0.94 kcal/mol,

Table 2). Moreover, the total reaction free energies calculated from the initial sequence 5′-TU•-3′ are 3.44−5.08 kcal/mol more negative than those for the whole C3′−O3′ bond rupture reaction. Thus, after hydrogen abstraction by the uracil-5-yl radical from the C2′ site of an adjacent 5′ nucleotide, the subsequent N1−C1′ bond cleavage is more preferred than the C3′−O3′ bond rupture from both the kinetic and thermodynamic points of view. In other words, the adjacent 5′ base release rather than DNA backbone breaks dominates electron attachment induced damage to single-stranded DNA incorporated by 5-halogenated deoxyuridines. All these theoretical predictions are well consistent with experimental observations that terminal thymine base release is the major damage pathway in the low energy electron bombarded T5BrUT oligonucleotides with DNA single-stranded breaks at the C3′−O3′ bond being the secondary one.18,65 P−O3′ Bond Breakage Following Hydrogen Abstraction from the Neighboring C3′ Position. After C3′-H abstraction, the spin density center is transferred to the adjacent C3′ site in 5′-•TC3′U-3′, making the nearby P−O3′ bond homolysis probable. At the transition state of the P−O3′ bond breakage (denoted as TS5, verified by having only one imaginary frequency 361.09i cm−1 and the IRC calculations), the P−O3′ bond length is extended to be 2.09 Å from a value of 1.63 Å in the reactant 5′-•TC3′U-3′ (Figure 5). The adjacent C3′−O3′ bond synchronously shrinks from 1.40 Å in 5′-•TC3′U3′ to 1.27 Å at the TS5 state and further decreases to be 1.22 Å (a representative CO double bond) in the bond rupture product Pro3. The Pro3 product is a ketone complexed with a phosphoryl radical stabilized by three hydrogen bonds. The other bond lengths are found to remain nearly unchanged along the P−O3′ bond cleavage process, as presented in Figure 5. The P−O3′ bond breakage is predicted to have the highest activation free energies among the three bonds considered here (19.47 kcal/mol in the gas phase and 19.87 kcal/mol in aqueous phase, Table 2). The P−O3′ bond cleavage reaction is slightly endothermic (1.63−3.82 kcal/mol), but the total reaction process starting from the sequence 5′-TU•-3′ is E


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than the stabilization energy (3.4 eV) of hydrated electrons.66 Therefore, besides low energy electrons (with energies < 4 eV) and prehydrated electrons, the DNA sequence 5′-TU•-3′ can even capture a hydrated electron forming the corresponding anion 5′-TU−-3′. The attached extra negative charge is distributed primarily on the uracil moiety with more than half (−0.52 in the gas phase and −0.57 in aqueous phase, Table S1) located at the C5 atom, making it a strong basic center for proton attack. Since the C2′− Hb bond direction in the optimized 5′-TU−-3′ anion is nearly antivertical to the uracil plane (Figure 6), hence, only the C2′−

thermodynamically favorable with the released reaction free energy being 19.61 kcal/mol in the gas phase and 16.83 kcal/ mol in aqueous solution (Table 2). Therefore, DNA backbone breaks are prone to occur at the C3′−O3′ bond with the P−O3′ bond being a minor damage site. This theoretical prediction is also in good agreement with the results of experimental studies on irradiated T5BrUT aqueous solutions.46 In brief, on the basis of the comparisons between the theoretical predictions and experimental observations, the mechanism involving hydrogen abstraction by the uracil-5-yl radical from the neighboring C2′ position followed by the N− glycosidic bond cleavage and the mechanisms involving hydrogen abstraction by the uracil-5-yl radical separately from the adjacent C 2′ and C 3′ positions followed by the corresponding C3′−O3′ and P−O3′ bond ruptures can be used to interpret the observed adjacent 5′ base release and DNA backbone breaks in radiated single-stranded DNA modified by 5BrdU or 5IdU, respectively. A recent theoretical study predicted that the isomer 6-bromo-2-deoxyuridine (6BrdU) would have better radiosensitizing action than 5BrdU since its free energy requirements for the ratecontrolling intranucleotide hydrogen transfer step were much lower.34 Our results, however, prove that the least energy requirement for the pathway involving internucleotide hydrogen abstraction from the C3′ site followed by the P−O3′ bond breakage (19.87 kcal/mol) is comparable to those for the pathways involving intranucleotide hydrogen transfer separately from the C3′ and C5′ sites followed by the P−O3′ and P−O5′ bond ruptures (18.90−23.50 kcal/mol). Further, while predicted to be the major bond rupture site therein,34 the P− O3′ bond is shown here to be only a minor rupture site leading to DNA single-stranded breaks. Therefore, on the basis of available data, the radiosensitizing action of 5BrdU is not weaker but stronger than its isomer 6BrdU. Proton Abstraction from the Neighboring C2′ Site Accompanied by C3′−O3′ Bond Rupture. The spin density in the DNA sequence 5′-TU•-3′ is found to be dominantly distributed on the C5 atom of the uracil moiety with a shape originating from the p-type orbital (Figures S1 and S2 in the Supporting Information), which is consistent with its electrondeficient feature. Undoubtedly, the species 5′-TU•-3′ has considerably high electron capture ability. As presented in Table 3, the vertical and adiabatic electron affinities (VEA and AEA) of 5′-TU•-3′ are calculated to be 2.33 and 3.00 eV in the gas phase, respectively. These electron attachment energies are separately enhanced to be 3.99 and 4.39 eV when solvent effects are taken into account. Notably, the aqueous phase VEA and AEA of 5′-TU•-3′ are separately 0.59 and 0.99 eV larger

Figure 6. Optimized structures for stationary points along the electron induced C3′−O3′ bond rupture pathway in the sequence 5′-TU•-3′. Distances are in Å.

Ha proton is considered here for subsequent internucleotide proton abstraction. It is found that the C2′−Ha proton transfer is accompanied by the C3′−O3′ bond rupture, a situation similar to those observed in previous studies.49,50 At the located transition state (TS6, verified by having only one imaginary frequency 1381.5i cm−1 and the IRC calculations), the transferred proton is 1.42 Å away from the C2′ site and 1.42 Å to the neighboring C5 atom. The C3′−O3′ bond length is elongated sufficiently to 1.54 Å from a value of 1.47 Å in the 5′TU−-3′ anion while the C2′−C3′ bond length is shortened from 1.53 to 1.49 Å (Figure 6). The highest occupied molecular orbital (HOMO) of the 5′-TU−-3′ anion mainly consists of the p-type orbital of the C5 atom of the uracil moiety while the HOMO of the TS6 state is mixed primarily by the p-type orbital of the C5 atom of the uracil moiety, the π orbital of the C2′−C3′ bond in the neighboring 2′-deoxyribose moiety, and the σ* orbital of the C3′−O3′ bond in the neighboring 2′deoxyribose moiety (Figure 7 and Figure S3). Proton transfer induced electron occupation on the bonding π orbital of the C2′−C3′ bond and the antibonding σ* orbital of the C3′−O3′ bond are considered to be responsible for these corresponding

Table 3. Electron Attachment and Detachment Energies of the DNA Sequence 5′-TU•-3′ as Well as Activation (ΔG*) and Reaction (ΔG) Free Energies for the C3′−O3′ Bond Rupture in 5′-TU−-3′ vacuum solution

VEAa

AEAb

VDEc

ΔG*

ΔG

2.33 3.99

3.00 (3.02) 4.39

3.62 4.94

8.72 12.28

−68.35 −62.11

VEA = Eneutral − Eanion, based on the optimized neutral structure. AEA = Eneutral − Eanion, based on respective optimal structure. Zeropoint-corrected values are given in parentheses. cValues for corresponding anions. VDE = Eneutral − Eanion, based on the optimized anionic structure. a b

F


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Figure 7. Gas phase HOMOs of relevant stationary points along the electron attachment induced C3′−O3′ bond rupture pathway in the sequence 5′TU•-3′.

breaks are mainly attributed to the C3′−O3′ bond rupture following the C2′-Ha abstraction with the P−O3′ bond breakage following the C3′-H abstraction being only a minor pathway. The 5′-TU•-3′ sequence is predicted to be able to bind a hydrated electron, forming the 5′-TU−-3′ anion. Although the internucleotide C2′-Ha proton abstraction in 5′-TU−-3′ anion is found to be accompanied by the 5′ C3′−O3′ bond rupture, this electron induced C3′−O3′ bond breakage is only secondary in both the gas phase and aqueous solution. All these theoretical predictions are in good agreement with experimental observations confirming the rationality of the proposed mechanisms. A recent theoretical study proposed that the isomer 6BrdU would have better radiosensitivity than 5BrdU according to its much lower least free energy requirements for both P−O3′ and P−O5′ bond ruptures.34 By comparing the free energy requirements for related rate-controlling reaction steps, our current results, however, prove that the radiosensitizing action of 5BrdU is stronger instead of weaker than that of 6BrdU.

bond length changes. In the proton transferred product Pro4, the C3′−O3′ bond is completely broken and a typical double bond (1.33 Å) is formed for the C2′−C3′ bond (Figure 6). Natural population analysis shows that now the extra negative charge is mainly distributed on the phosphate group (Table S1). Table 3 also collects the activation and reaction free energies for this concerted process in both the gas phase and aqueous solution. The small free energy barrier (8.72 kcal/mol) and large reaction free energy release (68.35 kcal/mol) indicate that the electron induced C3′−O3′ bond rupture is feasible in the gas phase 5′-TU•-3′ species. The activation free energy requirement is increased to be 12.28 kcal/mol when polarizable surroundings are taken into account. This medium free energy requirement and large reaction free energy release (62.11 kcal/ mol) also imply that the electron induced C3′−O3′ bond rupture is feasible in aqueous phase 5′-TU•-3′ sequence. However, compared with the much lower free energy requirements for the internucleotide hydrogen abstractions by the uracil-5-yl radical from the neighboring C2′ and C3′ sites, a conclusion can be drawn that the electron induced C3′−O3′ bond rupture via a pathway of internucleotide proton transfer is only minor.

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ASSOCIATED CONTENT

S Supporting Information *

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpcb.5b11432. Spin density distribution of the DNA sequence 5′-TU•-3′ in the gas phase and aqueous solution; HOMOs of relevant stationary points along the electron attachment induced C3′−O3′ bond rupture pathway in the sequence 5′-TU•-3′ in aqueous solution; potential energy surfaces depicting the electron induced C3′−O3′ bond rupture in the DNA sequence 5′-TU•-3′ in the gas phase and aqueous solution; and natural population analysis-based charge distributions on different base moieties, sugar moieties, and phosphate group of stationary points along the electron attachment induced C3′−O3′ bond rupture process (PDF)

CONCLUSIONS Possible C3′−O3′, P−O3′, and N−glycosidic bond ruptures following hydrogen abstractions by the uracil-5-yl radical from the C2′ and C3′ positions of a neighboring nucleotide as well as possible electron induced C3′−O3′ bond rupture in the DNA sequence 5′-TU•-3′ are explored in the present study employing the DFT method. The calculated activation free energies for the C2′-Ha and C3′-H abstractions are comparable with the C2′-Ha abstraction kinetically more favorable (6.66 versus 8.12 kcal/mol in the gas phase and 3.97 versus 4.92 kcal/ mol in aqueous solution). Internucleotide C2′-Ha and C3′-H abstractions transfer the spin density center from the original C5 atom of the uracil moiety separately to the C2′ and C3′ sites of the adjacent 2′-deoxyribose moiety, making subsequent C3′− O3′ or N−glycosidic bond rupture and P−O3′ bond breakage feasible. Among the three bonds considered here, the free energy requirements for the N−glycosidic bond cleavage are predicted to be the lowest (14.49−15.49 kcal/mol), followed by those for the C3′−O3′ bond rupture (17.19−17.36 kcal/ mol), and the free energy requirements for the P−O3′ bond breakage are the highest (19.47−19.87 kcal/mol). In other words, the adjacent 5′ base release resulting from the N− glycosidic bond cleavage following the C2′-Ha abstraction by the formed uracil-5-yl radical dominates the electron induced damage to a single-stranded DNA modified by radiosensitizing 5-halogenated deoxyuridines. Single-stranded DNA backbone

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] (Y.B.). Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by NSFC (21373123, 21573128, and 20973101) and NSF (ZR2013BM027) of Shandong Province. A part of the calculations were carried out at National Supercomputer Center in Jinan, Shanghai Supercomputer G


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Center, and High-Performance Supercomputer Center at SDUChem.

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