OH Radical - ACS Publications

Article Cite This: J. Phys. Chem. B XXXX, XXX, XXX−XXX

pubs.acs.org/JPCB

Does 8‑Nitroguanine Form 8‑Oxoguanine? An Insight from Its Reaction with •OH Radical Kanika Bhattacharjee and P. K. Shukla* Department of Physics, Assam University, Silchar 788011, India S Supporting Information *

ABSTRACT: 8-Nitroguanine (8-nitroG) formed due to nitration of guanine base of DNA plays an important role in mutagenesis and carcinogenesis. In the present contribution, state-of-the-art quantum chemical calculations using M06-2X density functional and domain-based local pair natural orbitalcoupled cluster theory with single, double, and perturbative triple excitations (DLPNO-CCSD(T)) methods have been carried out to investigate the mechanism of reaction of •OH radical with 8-nitroG leading to the formation of 8-oxoguanine (8-oxoG) (one of the most mutagenic and carcinogenic derivatives of guanine) in gas phase and aqueous media. Calculations of barrier energies and rate constants involved in the addition reactions of •OH radical at different sites of 8-nitroguanine show that C8 and C2 sites are the most and least reactive sites, respectively. Relative stability and Boltzmann populations of adducts show that the adduct formed at the C8 site occurs predominantly in equilibrium. Our calculations reveal that 8-nitroG is very reactive toward •OH radical and is converted readily into 8-oxoG when attacked by •OH radicals, in agreement with available experimental observations.

1. INTRODUCTION 8-Oxoguanine (8-oxoG) and 8-nitroguanine (8-nitroG) being two major mutagenic products of guanine have been the subject of intense research for a long time.1−13 Both 8-oxoG and 8nitroG are endogenously generated due to reactions of guanine base of DNA with peroxynitrite anion (ONOO−) and other reactive nitrogen oxide species (RNOS).12,14−19 Additionally, 8oxoG is formed in living cells in a huge amount due to encounter of DNA with reactive oxygen species (ROS), such as • OH radical, •OOH radical, and 1O2.7,13,20,21 8-oxoG causes GC to TA and GC to CG transversion mutations due to its ability to pair with A as well as C during DNA replication.10,22 Moreover, it is known to cause several deleterious consequences, including ageing, neurodegenerative disorders, cell death, and cancer.3,9,23−27 It is reported that in addition to 8oxoG, formation of 8-nitroG from ONOO− and other RNOS may play an important role in inflammation-associated mutagenesis and carcinogenesis in mammalian cells.11,12,28−31 8-nitroG that causes different types of mutation and cancer is reported to be more devastating than 8-oxoG.28 8-nitroG plays an important role in inflammation-associated mutagenesis and carcinogenesis in mammalian cells.12,30,31 It is found to increase the number of abasic sites in DNA.12 Both 8-oxoG and 8-nitroG are reported to be highly reactive.24,32 Several experimental and theoretical studies on further modification of 8-oxoG by free radicals and various ROS/RNOS are available in the literature, which show that 8oxoG readily reacts with these agents and forms some more mutagenic and stable lesions, such as spiroiminodihydantoin (Sp) and guanidinohydantoin (Gh).33−40 It is recently reported © XXXX American Chemical Society

that 8-oxoG can get methylated by methylating agents such as CH3N2+.41 However, despite the importance and occurrence of 8-nitroG in living cells, reactions of 8-nitroG with chemical agents that are prevalent in living cells, such as free radicals, ROS/RNOS and methylating agents, have not been investigated extensively. Lee et al. found that the reaction of ONOO− with 8-nitroG can lead to formation of 8-oxoG and other 8-oxopurines.42 Lee et al.42 also proposed a mechanism on formation of 8-oxoG from reaction of 8-nitroG with •OH radical. In another experiment, it is found that 8-nitroguanosine cyclic monophosphate (8nitro-cGMP) reacts with H2S/hydrogen sulfide to form 8-SHcGMP.43,44 The 8-SH-cGMP is analogous to the 8-hydroxyguanosine cyclic monophosphate (8-OH-cGMP) that is a tautomer of 8-oxo-cGMP. These limited experimental studies indicate that 8-nitroG gets converted into 8-oxoG. Although not very clear, we believe that conversion of 8-nitroG to 8oxoG may be playing a vital role in mutagenesis and carcinogenesis caused by RNOS-induced DNA and tissue damage. Therefore, it is imperative to investigate the mechanisms of reactions of 8-nitroG with free radicals and ROS/RNOS forming 8-oxoG to understand if conversion of 8nitroG into 8-oxoG occurs efficiently in biological systems. Such studies will be useful in understanding how reactive is 8nitroG as well as in ascertaining the end products of DNA damage caused by ROS/RNOS that may contribute in Received: December 11, 2017 Revised: January 22, 2018 Published: January 23, 2018 A

DOI: 10.1021/acs.jpcb.7b12192 J. Phys. Chem. B XXXX, XXX, XXX−XXX

Article

The Journal of Physical Chemistry B

Table 1. Gibbs Free-Energy Barriers (ΔGb) and the Corresponding Enthalpy Changes (ΔHb) (kcal/mol) Involved in Addition Reactions of •OH Radical at the Different Sites of 8-nitroG, As Obtained at the Different Levels of Theory in Gas Phase and Aqueous Mediaa reaction sites level of theory M06-2X/6-31G(d,p) M06-2X/aug-cc-pVDZ//M06-2X/6-31G(d,p) M06-2X/aug-cc-pVDZ DLPNO-CCSD(T)/cc-pVDZ//M06-2X/6-31G(d,p) CPCM-DLPNO-CCSD(T)/cc-pVDZ//M06-2X/6-31G(d,p) rate constantb relative reactivityc

C2

C4

Gas Phase 13.94(4.06) 14.41(4.53) 14.26(4.45) 15.76(5.88) Aqueous Media 21.75(11.87) 6.90 × 10−4 1.34 × 10−5

C5

12.44(2.33) 12.43(2.32) 12.11(2.17) 15.19(5.08) 18.55(8.44) 1.54 × 10−1 2.98 × 10−3

C8

7.26(−2.63) 7.12(−2.76) 7.12(−2.77) 11.86(1.98) 13.83(3.95) 4.45 × 102 8.64

5.92(−3.69) 6.72(−2.89) 6.46(−2.98) 9.31(−0.30) 12.38(2.77) 5.15 × 103 100

a The ΔHb values are given in parentheses. bRate constant is calculated using ΔGb obtained at the CPCM-DLPNO-CCSD(T)/cc-pVDZ level of theory in aqueous media. cRelative reactivity with respect to C8 site is calculated using rate constants.

Table 2. Relative Gibbs Free Energies (kcal/mol) and Relative Boltzmann Population of Adducts Formed Due to Addition of • OH Radical at the Different Sites of 8-nitroG, as Obtained at the Various Levels of Theory in Gas Phase and Aqueous Mediaa adducts level of theory M06-2X/aug-cc-pVDZ//M06-2X/6-31G(d,p) DLPNO-CCSD(T)/cc-pVDZ//M06-2X/6-31G(d,p) CPCM-DLPNO-CCSD(T)/cc-pVDZ//M06-2X/6-31G(d,p) a

C2 Gas Phase 20.54(8.57 × 10−16) 13.96(5.79 × 10−11) Aqueous Media 18.63(2.16 × 10−14)

C4

C5

C8

23.11(1.11 × 10−17) 21.33(2.26 × 10−16)

26.67(2.85 × 10−20) 25.61(1.63 × 10−19)

0.0(1) 0.0(1)

34.58(4.34 × 10−26)

29.81(1.37 × 10−22)

0.0(1)

Relative Boltzmann populations are given in parentheses.

developing effective drugs for the treatment of mutation and cancer caused by DNA damage. In the wake of the above-mentioned facts and that the •OH radical that is a main radical formed from radiolysis of water or from a chemical source in living cells is considered to be one of the most devastating ROS causing excessive formation of 8oxoG and other guanine derivatives in biological media,13,20,45,46 we have investigated here theoretically the mechanism of reaction of 8-nitroG with •OH radical, leading to formation of 8-oxoG, employing state-of-the-art quantum chemical methods.

Full geometry optimization and vibrational frequency analysis of reactants, intermediate complexes (ICs), and product complexes (PCs), as well as transition states (TSs) involved in the reaction of •OH radical with 8-nitroG were carried out at the M06-2X/6-31G(d,p) level of theory in gas phase. These calculations were followed by single-point energy calculations at the M06-2X/aug-cc-pVDZ level of theory in gas phase. Energetics involved in the addition reactions of •OH radical at different sites of 8-nitroG were also calculated by fully optimizing geometries of corresponding stationary points at the M06-2X/aug-cc-pVDZ level of theory in gas phase to see the effect of geometry optimization using larger basis set on energetics. Finally, single-point energy calculations on all of the M06-2X/6-31G(d,p) optimized species were carried out at the DLPNO-CCSD(T)/cc-pVDZ level of theory in gas phase and aqueous phase to obtain more accurate energies. It may be noted that the DFT and DLPNO-CCSD(T) calculations have been carried out for •OH radical and all ICs, PCs, and TSs under unrestricted formalism, whereas for 8-nitroG under restricted formalism. The solvent effect of aqueous media was estimated using the conductor-like polarizable continuum model (CPCM),60,61 as implemented in ORCA (4.0.1) code. Thermal corrections to enthalpies and Gibbs free energies determined at 298.15 K using the M06-2X/6-31G(d,p) level of theory were also applied to the total energies obtained by single-point energy calculations to obtain enthalpies and Gibbs free energies in both gas phase and aqueous media. The Gauss View program was used for visualization of structures and vibrational modes.62 The rate constants of reactions at the different sites were calculated using transition state theory

2. COMPUTATIONAL DETAILS The mechanism of reaction of •OH radical with 8-nitroG leading to the formation of 8-oxoG has been investigated theoretically using the M06-2X functional47 of density functional theory (DFT), as implemented in the Gaussian09 software suite48 and the recently developed domain-based local pair natural orbital-coupled cluster theory with single, double, and perturbative triple excitations (DLPNO-CCSD(T)), as implemented in the ORCA (4.0.1) quantum chemistry code.49 The DLPNO-CCSD(T) method developed by Neese and coworkers50−55 has been found to deliver results for both closedand open-shell systems, in close agreement to the gold standard method of quantum chemistry [CCSD(T)] at moderate computational cost. The M06-2X functional of DFT developed by Truhlar’s group is reported to be a better functional than the most popular and widely used B3LYP functional for the study of relative stability of conformers, noncovalent interactions, barrier energies, rate constants, and for thermochemistry of a wide variety of molecular systems.56−59

rate constant = B

KbT −ΔGb / RT e h DOI: 10.1021/acs.jpcb.7b12192 J. Phys. Chem. B XXXX, XXX, XXX−XXX

Article


Figure 1. Potential energy profiling, including gas phase M06-2X/6-31G(d,p) optimized structures along with certain interatomic distances (Å) of TSs and adducts involved in addition reactions of •OH radical at the C2, C4, C5, and C8 sites of 8-nitroG. The relative Gibbs free energies (kcal/ mol) determined at the CPCM-DLPNO-CCSD(T)/cc-pVDZ//M06-2X/6-31G(d,p) level of theory in aqueous media are also shown.

where ΔGb = Gibbs free-energy barrier and other symbols have usual meanings.

determined at the M06-2X/aug-cc-pVDZ//M06-2X/6-31G(d,p) level are almost similar to those determined by full optimization at the M06-2X/aug-cc-pVDZ level (Table 1). It shows that geometry optimizations using the 6-31G(d,p) and aug-cc-pVDZ basis sets yield similar results in the present study. It is evident from Table 1 that values of ΔGb and ΔHb for addition reactions of •OH radical at different sites of 8-nitroG increase in the following order: C8 < C5 < C4 < C2, at different levels of theory in gas phase. Their values in gas phase calculated using DLPNO-CCSD(T) method are greater (∼1.4−4.7 kcal/mol) than those calculated using M06-2X density functional (Table 1). In aqueous media, the ΔGb and ΔHb follow the same trend as in gas phase but their values are increased (Table 1). The ΔGb values for addition reactions at the C8, C5, C4, and C2 sites calculated at the DLPNOCCSD(T) level of theory in gas phase (aqueous media) are found to be 9.31(12.38), 11.86(13.83), 15.19(18.55), and 15.76(21.75) kcal/mol, respectively (Table 1). It is noted that ΔHb values are significantly smaller (9.6−10.1 kcal/mol) than their corresponding ΔGb values (Table 1). It shows that the effect of entropy in barrier energies of addition reactions of • OH radical at different sites of 8-nitroG is appreciable. The rate constant and relative reactivity indicate that the C8 site as compared to other sites of 8-nitroG is far more reactive, its rate constant being 5.15 × 103 s−1 at the CPCM-DLPNOCCSD(T)/cc-pVDZ level in aqueous media (Table 1).

3. RESULTS AND DISCUSSION 3.1. Addition Reactions of •OH Radical at Different Sites of 8-nitroG. The Gibbs free-energy barriers (ΔGb) and the corresponding enthalpy changes (ΔHb) for addition reactions of •OH radical at the C2, C4, C5, and C8 sites of 8-nitroG determined at different levels of theory in gas phase and aqueous media are presented in Table 1. The rate constants calculated using ΔGb obtained at the CPCM-DLPNO-CCSD(T)/cc-pVDZ level of theory in aqueous media and thereby relative reactivities of various sites calculated with respect to that for the C8 site are also presented in Table 1. The relative stability and relative Boltzmann populations of •OH radical adducts formed at different sites of 8-nitroG are presented in Table 2. The potential energy profiling, including gas phase M06-2X/6-31G(d,p) optimized structures of TSs and adducts involved in addition reactions of 8-nitroG, is displayed in Figure 1. The •OH radical is found to be located above the plane of the ring of 8-nitroG in all TSs, the distance between the •OH radical and reaction sites of 8-nitroG lies in the range of 1.925− 2.071 Å (Figure 1). It is found that 8-nitroG ring loses its planarity and gets distorted appreciably in adducts formed at the C2, C4, and C5 sites of 8-nitroG (Figure 1). Table 1 shows that ΔGb and ΔHb values for addition of •OH radical at all sites of 8-nitroG do not change substantially in going from 631G(d,p) to aug-cc-pVDZ basis set. Further, these values C


Article


Scheme 1. Formation of PC1 [8-oxoG + NO2] Starting from the Adduct of •OH Radical at the C8 Site of 8-nitroG [C8OH−8nitroG]a

a

The Gibbs free-energy barriers (ΔGb) and released energies (ΔGr) (kcal/mol) of different steps, as obtained at the CPCM-DLPNO-CCSD(T)/ccpVDZ//M06-2X/6-31G(d,p) level in aqueous media are given. Mulliken charges (in the unit of magnitude of electronic charge) are also shown.

steps calculated using ΔGb obtained at CPCM-DLPNOCCSD(T)/cc-pVDZ level in aqueous media are also presented in Table 3. Scheme 1 showing formation of PC1 (a complex of 8-oxoG and NO2) from C8OH−8-nitroG adduct is a four-step reaction process involving transition states TS1−TS4 and intermediate complexes IC1−IC3. At the first step of Scheme 1, rupture of the bond between NO2 moiety and the C8 site of 8-nitroG takes place. The distance between the two at TS1 is 1.959 Å (Scheme 1). The intermediate complex, IC1, formed in the first step is a complex of 8-hydroxyguanine (8-hydroxyG) and NO2. 8-Hydroxyguanine (8-hydroxyG) is known to be a tautomer of 8-oxoG.63 In going from IC1 to IC2 through TS2, the NO2 moiety abstracts the H12 atom of 8-hydroxyG, forming 8-oxoG radical and HNO2, as the Mulliken charges (in the unit of magnitude of electronic charge) on the two are only 0.054 and −0.054 (Scheme 1). At TS2, the O11H12 and H12O8b distances are 1.116 and 1.30 Å, respectively (Scheme 1). Both IC2 and IC3 are complexes of 8-oxoG radical [8-oxoG(-H7)] and HNO2 moiety (Scheme 1), as step 3 only involves rotation of HNO2 moiety from O8 to N7 site and H-atom of HNO2 is pointed toward the N7 site in IC3 (Scheme 1). At the last step of Scheme 1, the H-atom of the HNO2 moiety moves and gets attached to the N7 site of 8-oxoG(-H7) radical in IC3, leading to the formation 8-oxoG complexed with NO2 moiety (PC1). The O8bH12 and H12N7 distances at TS4 of 8-nitroG are found to be 1.307 and 1.173 Å, respectively. Thus, steps 2−4 of Scheme 1 merely show the structural transformation of 8hydroxyG to 8-oxoG mediated by the NO2 moiety. For Scheme 1 of reactions involving 8-nitroG, the values of ΔGb1, ΔGb2, ΔGb3, and ΔGb4 determined at the DLPNOCCSD(T) level of theory in gas phase (aqueous media) are found to be 3.03(4.48), 25.63(9.47), 0.66(0.53), and 28.77(15.08) kcal/mol, respectively (Table 3). The corre-

The Gibbs free energy of adducts formed at different sites of 8-nitroG in gas phase increases in the following order: C8 < C2 < C4 < C5, whereas that in aqueous media increases in the following order: C8 < C2 < C5 < C4 (Table 2). The gas phase (aqueous media) free energy of the adduct formed at the C2 site is 13.96(18.63) kcal/mol higher than that at the C8 site, as obtained at the DLPNO-CCSD(T)/cc-pVDZ level of theory, making its equilibrium Boltzmann population negligible (5.79 × 10−11 (2.16 × 10−14)) (Table 2). The populations of adducts at C4 and C5 sites are even smaller (Table 2). Thus, the adduct formed at the C8 site is predominant. Further, the addition reaction at the C8 site is found to be highly exothermic (−34.23 kcal/mol) at the DLPNO-CCSD(T)/cc-pVDZ level of theory in aqueous media (Table S1 of Supporting Information). In view of the above discussion, it is clear that the C8 site of 8-nitroG is the most favorable site for addition of • OH radical in both gas phase and aqueous media. 3.2. Mechanism of Formation of 8-oxoG. As discussed in the preceding section, we note that formation of •OH radical adduct at the C8 site of 8-nitroG (C8OH−8-nitroG) is a prerequisite for the formation of 8-oxoG due to reaction of • OH radical with 8-nitroG. Formation of 8-oxoG starting from C8OH−8-nitroG adduct can occur via three different reaction mechanisms, as shown in Schemes 1−3. The structures of the intermediate complexes (ICs), transition states (TSs), and product complexes (8-oxoG + NO2) along with certain optimized geometrical parameters obtained at the M06-2X/631G(d,p) level in gas phase and the Gibbs free-energy barriers (ΔGb) and released energies (ΔGr) of reactions calculated at the CPCM-DLPNO-CCSD(T)/cc-pVDZ level in aqueous media are displayed in Schemes 1−3. The ΔGb and ΔGr at different steps of reactions of •OH radical with 8-nitroG shown in Schemes 1−3 calculated at various levels of theory in gas and aqueous media, are listed in Table 3. Rate constants of different D


a

2.73(2.55) −13.74(−10.90) 11.65(9.87) −19.60(−17.86) 1.03(0.96) −2.48(−1.45) 20.18(18.42) −20.37(−19.47)

36.36(36.18) −57.67(−52.66)

42.58(42.84) −51.99(−52.01)

ΔGb1(ΔHb1) ΔGr1(ΔHr1) ΔGb2(ΔHb2) ΔGr2(ΔHr2) ΔGb3(ΔHb3) ΔGr3(ΔHr3) ΔGb4(ΔHb4) ΔGr4(ΔHr4)

ΔGb5(ΔHb5) ΔGr5(ΔHr5)

ΔGb6(ΔHb6) ΔGr6(ΔHr6)

Scheme 1 3.03(2.85) −22.06(−19.23) 25.62(23.84) −30.79(−29.04) 0.66(0.59) −2.65(−1.63) 28.77(27.01) −30.36(−29.47) Scheme 2 36.63(36.45) −64.42(−60.41) Scheme 3 42.54(42.80) −51.29(−51.31)

DLPNO-CCSD(T)/cc-pVDZ//M06-2X/6-31G(d,p)

gas phase

aqueous media

42.76(43.01) −52.72(−52.74)

35.64(35.47) −60.08(−56.07)

4.48(4.30) −17.14(−14.31) 9.47(7.69) −22.84(−21.09) 0.53(0.45) −2.63(−1.60) 15.08(13.32) −9.08(−8.18)

CPCM-DLPNO-CCSD(T)/cc-pVDZ//M06-2X/6-31G(d,p)

The enthalpy values are given in parentheses. bThe rate constant is calculated using ΔGb obtained at the CPCM-DLPNO-CCSD(T)/cc-pVDZ level of theory in aqueous media.

M06-2X/aug-cc-pVDZ//M06-2X/6-31G(d,p)

energies

2.68 × 10−19

4.47 × 10−14

5.39 × 101

2.54 × 1012

7.02 × 105

3.21 × 109

rate constant (s−1)b

Table 3. Gibbs Free-Energy Barriers (ΔGb) and Released Energies (ΔGr) and the Corresponding Enthalpy Changes (ΔHb and ΔHr) (kcal/mol) Involved in Various Steps of Schemes 1−3 of the Reaction of •OH Radical with 8-nitroG, as Obtained at Different Levels of Theory in Gas Phase and Aqueous Mediaa

The Journal of Physical Chemistry B Article

E


Article


Scheme 2. Formation of PC2 [8-oxoG + NO2] Starting from the Adduct of •OH Radical at the C8 Site of 8-nitroG [C8OH−8nitroG]a

a

The Gibbs free-energy barrier (ΔGb) and released energy (ΔGr) (kcal/mol), as obtained at the CPCM-DLPNO-CCSD(T)/cc-pVDZ//M06-2X/631G(d,p) level in aqueous media, are given. Mulliken charges (in the unit of magnitude of electronic charge) are also shown.

sponding ΔGr in gas phase (aqueous media) are found to be −22.06(−17.14), −30.79(−22.84), −2.65(−2.63), and −30.36(−9.08) kcal/mol, respectively (Scheme 1 and Table 3). This shows overall Scheme 1 is exothermic (Table 3). The values of Gibbs free energies and enthalpy changes show that entropy does not play any significant role in reaction Scheme 1 (Table 2). The rate constant of the first step of Scheme 1 is highest 3.21 × 109 s−1, indicating that formation of 8-hydroxyG (as in complex IC1) according to Scheme 1 would take place rapidly. According to Scheme 2, in going from C8OH−8-nitroG adduct to PC2 via TS5, the H-atom of OH radical bonded to the C8 site of the 8-nitroG moves and gets attached to the N7 site of guanine and consequently the NO2 moiety gets detached. Scheme 3 shows formation of PC3 from IC1 without involvement of NO2 group. It is to be noted that the product complexes PC1−PC3 are complexes of 8-oxoG and NO2 with different orientation of NO2 in the complexes (Schemes 1−3). Thus, PC1−PC3 are almost the same. The negative vibration at TS6 shows movement of H12 atom directly from O11 to N7 site (Scheme 3). Schemes 2 and 3 are also found to be exothermic, but the barriers in these schemes, i.e., ΔGb5 and ΔGb6, are noted to be very high, their values at DLPNOCCSD(T)/cc-pVDZ level of theory in gas phase (aqueous media) being 36.63(35.64) and 42.54(42.76) kcal/mol, respectively (Table 3). A summary of Schemes 1−3 starting from addition of •OH radical at the C8 site of 8-nitroG is presented in Figure 2. The relative Gibbs free energies of different stationary points involved in Schemes 1−3, calculated with respect to the sum of Gibbs free energies of reactants (8-NO2G + •OH radical) at the

CPCM-DLPNO-CCSD(T)/cc-pVDZ level in aqueous media, are also presented in Figure 2. However, the relative energywise locations of the different stationary points shown in this figure are only qualitative and not to scale. It is clear from Figure 2 that TSs, ICs, and PC1 of Scheme 1, excepting the TS showing addition of •OH radical at the C8 site (TSC8), which is common to all schemes, have lower energies with respect to the sum of Gibbs free energies of reactants (8-NO2G + •OH radical). However, TSs in Schemes 2 and 3 have very high energies. Thus, it is evident from Figure 2 that formation of 8oxoG would occur preferably following Scheme 1. 3.3. Biological Implications. Water plays an important role in the biological reactions. Therefore, in addition to the implicit bulk solvent effect of a water molecule treated using CPCM, the role of a single water molecule as a catalyst in the addition reaction of •OH radical at the C8 site of 8-nitroG, which is a prerequisite for formation of 8-oxoG, has been investigated. The gas phase M06-2X/6-31G(d,p) optimized structures of the reactant complex, transition state, and adduct, along with certain optimized geometrical parameters and the ΔGb and ΔGr values determined at the DLPNO-CCSD(T)/ccpVDZ//M06-2X/6-31G(d,p) level in gas phase and aqueous media involved in the addition of •OH radical at the C8 site of 8-nitroG in presence of a water molecule are shown in Figure 3. The ΔGb and ΔGr for this reaction in gas phase (aqueous media) were found to be 6.65(5.25) and −37.78(−38.56), respectively (Figure 3). The corresponding ΔGb in absence of a specific water molecule was 9.31(12.38) kcal/mol in gas phase (aqueous media) (Table 1). This indicates that the presence of a specific water molecule reduces appreciably the barrier for F


Article

The Journal of Physical Chemistry B Scheme 3. Formation of PC3 [8-oxoG + NO2] Starting from the Intermediate Complex (IC1) Formed in Scheme 1a

a

The Gibbs free-energy barrier (ΔGb) and released energy (ΔGr) (kcal/mol), as obtained at the CPCM-DLPNO-CCSD(T)/cc-pVDZ//M06-2X/631G(d,p) level in aqueous media are given. Mulliken charges (in the unit of magnitude of electronic charge) are also shown.

Figure 2. Summary of Schemes 1−3 involved in the reaction of 8-nitroG and •OH radical. The relative Gibbs free energies (kcal/mol) of different species with respect to the sum of the Gibbs free energies of reactants (8-nitroG + OH) obtained at the CPCM-DLPNO-CCSD(T)/cc-pVDZ// M06-2X/6-31G(d,p) level in aqueous media are given.

addition of •OH radical at the C8 site of 8-nitroG and hence would facilitate the formation of 8-oxoG.

radical with 8-nitroG, leading to the formation of 8-oxoG in gas phase and aqueous media. Calculations of Gibbs free-energy barriers and rate constants involved in the addition reaction of • OH radical at different sites of 8-nitroG at the DLPNOCCSD(T)/cc-pVDZ//M06-2X/6-31G(d,p) level of theory in both gas phase and aqueous media reveal that C8 and C2 sites are, respectively, the most and least reactive sites for addition of

4. CONCLUSIONS State-of-the-art quantum chemical calculations using M06-2X density functional and DLPNO-CCSD(T) method have been carried out to investigate the mechanism of the reaction of •OH G


Article


Figure 3. Optimized structures of reaction coordinate, TS, and adduct involved in the addition of •OH radical at C8 site of 8-nitroG in the presence of a water molecule. The Gibbs free-energy barrier (ΔGb) and released energy (ΔGr) (kcal/mol), as obtained at the CPCM-DLPNO-CCSD(T)/ccpVDZ//M06-2X/6-31G(d,p) level of theory in gas (aqueous media), are also given. •

OH radical. Relative stability and Boltzmann populations of adducts show that the adduct formed at the C8 site occurs predominantly in equilibrium. Formation of 8-oxoG from 8nitroG can occur following three paths, as shown in Schemes 1−3. Scheme 1 is found to be most feasible. The presence of a specific water molecule is found to facilitate the addition of • OH radical at the C8 site of 8-nitroG and thereby formation of 8-oxoG. Our present calculations show that 8-nitroG is very reactive toward •OH radical and would convert readily into 8oxoG in biological media.

■

■

Boltzmann population of adducts formed by addition of OH radical at different sites of guanine (PDF)

•

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected], [email protected]. in. ORCID

P. K. Shukla: 0000-0002-4664-4130 Notes

The authors declare no competing financial interest.

■ ■

ASSOCIATED CONTENT

S Supporting Information *

ACKNOWLEDGMENTS This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpcb.7b12192. Gibbs free reaction energies and corresponding enthalpy changes (kcal/mol) involved in addition reactions of • OH radical at different sites of 8-nitroG, as obtained at various levels of theory (Table S1); definitions of the Gibbs free-energy barrier (ΔGb) and released energy (ΔG r ) of a reaction step used in the present contribution; formula used for calculation of the relative

REFERENCES

(1) Helbock, H. J.; Beckman, K. B.; Shigenaga, M. K.; Walter, P. B.; Woodall, A. A.; Yeo, H. C.; Ames, B. N. DNA Oxidation Matters: The Hplc−Electrochemical Detection Assay of 8-Oxo-Deoxyguanosine and 8-Oxo-Guanine. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 288−293. (2) Ishii, Y.; Ogara, A.; Okamura, T.; Umemura, T.; Nishikawa, A.; Iwasaki, Y.; Ito, R.; Saito, K.; Hirose, M.; Nakazawa, H. Development

H


Article


Carcinogenesis and Aging. Mutat. Res., Rev. Mutat. Res. 2001, 488, 65−76. (22) Kino, K.; Sugiyama, H. Possible Cause of G· C → C· G Transversion Mutation by Guanine Oxidation Product, Imidazolone. Chem. Biol. 2001, 8, 369−378. (23) Asami, S.; Hirano, T.; Yamaguchi, R.; Tomioka, Y.; Itoh, H.; Kasai, H. Increase of a Type of Oxidative DNA Damage, 8Hydroxyguanine, and Its Repair Activity in Human Leukocytes by Cigarette Smoking. Cancer Res. 1996, 56, 2546−2549. (24) Kim, J.-E.; Choi, S.; Yoo, J.-A.; Chung, M.-H. 8-Oxoguanine Induces Intramolecular DNA Damage but Free 8-Oxoguanine Protects Intermolecular DNA from Oxidative Stress. FEBS Lett. 2004, 556, 104−110. (25) Kono, Y.; Nakamura, K.; Kimura, H.; Nishii, N.; Watanabe, A.; Banba, K.; Miura, A.; Nagase, S.; Sakuragi, S.; Kusano, K. F.; et al. Elevated Levels of Oxidative DNA Damage in Serum and Myocardium of Patients with Heart Failure. Circ. J. 2006, 70, 1001−1005. (26) Sato, S.; Mizuno, Y.; Hattori, N. Urinary 8-Hydroxydeoxyguanosine Levels as a Biomarker for Progression of Parkinson Disease. Neurology 2005, 64, 1081−1083. (27) Sliwinska, A.; Kwiatkowski, D.; Czarny, P.; Toma, M.; Wigner, P.; Drzewoski, J.; Fabianowska-Majewska, K.; Szemraj, J.; Maes, M.; Galecki, P.; et al. The Levels of 7, 8-Dihydrodeoxyguanosine (8-Oxog) and 8-Oxoguanine DNA Glycosylase 1 (Ogg1)−a Potential Diagnostic Biomarkers of Alzheimer’s Disease. J. Neurol. Sci. 2016, 368, 155−159. (28) Bhamra, I.; Compagnone-Post, P.; O’Neil, I. A.; Iwanejko, L. A.; Bates, A. D.; Cosstick, R. Base-Pairing Preferences, Physicochemical Properties and Mutational Behaviour of the DNA Lesion 8Nitroguanine. Nucleic Acids Res. 2012, 40, 11126−11138. (29) Ma, N.; Tagawa, T.; Hiraku, Y.; Murata, M.; Ding, X.; Kawanishi, S. 8-Nitroguanine Formation in Oral Leukoplakia, a Premalignant Lesion. Nitric Oxide 2006, 14, 137−143. (30) Hiraku, Y. Formation of 8-Nitroguanine, a Nitrative DNA Lesion, in Inflammation-Related Carcinogenesis and Its Significance. Environ. Health Prev. Med. 2010, 15, 63−72. (31) Kawanishi, S.; Hiraku, Y.; Pinlaor, S.; Ma, N. Oxidative and Nitrative DNA Damage in Animals and Patients with Inflammatory Diseases in Relation to Inflammation-Related Carcinogenesis. Biol. Chem. 2006, 387, 365−372. (32) Steenken, S.; Jovanovic, S. V.; Bietti, M.; Bernhard, K. The Trap Depth (in DNA) of 8-Oxo-7, 8-Dihydro-2 ‘Deoxyguanosine as Derived from Electron-Transfer Equilibria in Aqueous Solution. J. Am. Chem. Soc. 2000, 122, 2373−2374. (33) Burrows, C. J.; Muller, J. G.; Kornyushyna, O.; Luo, W.; Duarte, V.; Leipold, M. D.; David, S. S. Structure and Potential Mutagenicity of New Hydantoin Products from Guanosine and 8-Oxo-7, 8Dihydroguanine Oxidation by Transition Metals. Environ. Health Perspect. 2002, 110, 713. (34) Fleming, A. M.; Muller, J. G.; Dlouhy, A. C.; Burrows, C. J. Structural Context Effects in the Oxidation of 8-Oxo-7, 8-Dihydro-2′Deoxyguanosine to Hydantoin Products: Electrostatics, Base Stacking, and Base Pairing. J. Am. Chem. Soc. 2012, 134, 15091−15102. (35) Gremaud, J. N.; Martin, B. D.; Sugden, K. D. Influence of Substrate Complexity on the Diastereoselective Formation of Spiroiminodihydantoin and Guanidinohydantoin from Chromate Oxidation. Chem. Res. Toxicol. 2010, 23, 379−385. (36) Hah, S. S.; Kim, H. M.; Sumbad, R. A.; Henderson, P. T. Hydantoin Derivative Formation from Oxidation of 7, 8-Dihydro-8Oxo-2′-Deoxyguanosine (8-Oxodg) and Incorporation of 14 CLabeled 8-Oxodg into the DNA of Human Breast Cancer Cells. Biorg. Med. Chem. Lett. 2005, 15, 3627−3631. (37) Jia, L.; Shafirovich, V.; Shapiro, R.; Geacintov, N. E.; Broyde, S. Spiroiminodihydantoin Lesions Derived from Guanine Oxidation: Structures, Energetics, and Functional Implications. Biochemistry 2005, 44, 6043−6051. (38) Munk, B. H.; Burrows, C. J.; Schlegel, H. B. An Exploration of Mechanisms for the Transformation of 8-Oxoguanine to Guanidinohydantoin and Spiroiminodihydantoin by Density Functional Theory. J. Am. Chem. Soc. 2008, 130, 5245−5256.

of Quantitative Analysis of 8-Nitroguanine Concomitant with 8Hydroxydeoxyguanosine Formation by Liquid Chromatography with Mass Spectrometry and Glyoxal Derivatization. J. Pharm. Biomed. Anal. 2007, 43, 1737−1743. (3) Loft, S.; Fischer-Nielsen, A.; Jeding, I. B.; Vistisen, K.; Poulsen, H. E. 8-Hydroxydeoxyguanosine as a Urinary Biomarker of Oxidative DNA Damage. J. Toxicol. Environ. Health 1993, 40, 391−404. (4) Wood, M. L.; Esteve, A.; Morningstar, M. L.; Kuziemko, G. M.; Essigmann, J. M. Genetic Effects of Oxidative DNA Damage: Comparative Mutagenesis of 7, 8-Dihydro-8-Oxoguanine and 7, 8Dihydro-8-Oxoadenine in Escherichia Coli. Nucleic Acids Res. 1992, 20, 6023−6032. (5) Shigenaga, M. K.; Gimeno, C. J.; Ames, B. N. Urinary 8-Hydroxy2′-Deoxyguanosine as a Biological Marker of in Vivo Oxidative DNA Damage. Proc. Natl. Acad. Sci. U.S.A. 1989, 86, 9697−9701. (6) Kirouac, K. N.; Ling, H. Unique Active Site Promotes Error-Free Replication Opposite an 8-Oxo-Guanine Lesion by Human DNA Polymerase Iota. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 3210−3215. (7) Shukla, P. K.; Mishra, P. C. H2O3 as a Reactive Oxygen Species: Formation of 8-Oxoguanine from Its Reaction with Guanine. J. Phys. Chem. B 2007, 111, 4603−4615. (8) Shukla, P. K.; Jena, N. R.; Mishra, P. C. Quantum Theoretical Study of Molecular Mechanisms of Mutation and Cancer-a Review. Proc. Natl. Acad. Sci., India, Sect. A 2011, 81, 79−98. (9) Neeley, W. L.; Essigmann, J. M. Mechanisms of Formation, Genotoxicity, and Mutation of Guanine Oxidation Products. Chem. Res. Toxicol. 2006, 19, 491−505. (10) Bruner, S. D.; Norman, D. P.; Verdine, G. L. Structural Basis for Recognition and Repair of the Endogenous Mutagen 8-Oxoguanine in DNA. Nature 2000, 403, 859. (11) Suzuki, N.; Yasui, M.; Geacintov, N. E.; Shafirovich, V.; Shibutani, S. Miscoding Events During DNA Synthesis Past the Nitration-Damaged Base 8-Nitroguanine. Biochemistry 2005, 44, 9238−9245. (12) Yermilov, V.; Rubio, J.; Ohshima, H. Formation of 8Nitroguanine in DNA Treated with Peroxynitrite in Vitro and Its Rapid Removal from DNA by Depurination. FEBS Lett. 1995, 376, 207−210. (13) Jena, N. R.; Mishra, P. C. Mechanisms of Formation of 8Oxoguanine Due to Reactions of One and Two Oh• Radicals and the H2o2 Molecule with Guanine: A Quantum Computational Study. J. Phys. Chem. B 2005, 109, 14205−14218. (14) Inoue, S.; Kawanishi, S. Oxidative DNA Damage Induced by Simultaneous Generation of Nitric Oxide and Superoxide. FEBS Lett. 1995, 371, 86−88. (15) Yermilov, V.; Yoshie, Y.; Rubio, J.; Ohshima, H. Effects of Carbon Dioxide/Bicarbonate on Induction of DNA Single-Strand Breaks and Formation of 8-Nitroguanine, 8-Oxoguanine and BasePropenal Mediated by Peroxynitrite. FEBS Lett. 1996, 399, 67−70. (16) Szabó, C.; Ohshima, H. DNA Damage Induced by Peroxynitrite: Subsequent Biological Effects. Nitric Oxide 1997, 1, 373−385. (17) Shukla, P. K.; Mishra, P. C. Catalytic Involvement of Co2 in the Mutagenesis Caused by Reactions of Onoo-with Guanine. J. Phys. Chem. B 2008, 112, 4779−4789. (18) Sodum, R. S.; Fiala, E. S. Analysis of Peroxynitrite Reactions with Guanine, Xanthine, and Adenine Nucleosides by High-Pressure Liquid Chromatography with Electrochemical Detection: C8-Nitration and-Oxidation. Chem. Res. Toxicol. 2001, 14, 438−450. (19) Burney, S.; Niles, J. C.; Dedon, P. C.; Tannenbaum, S. R. DNA Damage in Deoxynucleosides and Oligonucleotides Treated with Peroxynitrite. Chem. Res. Toxicol. 1999, 12, 513−520. (20) Bergeron, F.; Auvré, F.; Radicella, J. P.; Ravanat, J.-L. Ho• Radicals Induce an Unexpected High Proportion of Tandem Base Lesions Refractory to Repair by DNA Glycosylases. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 5528−5533. (21) Kawanishi, S.; Hiraku, Y.; Oikawa, S. Mechanism of GuanineSpecific DNA Damage by Oxidative Stress and Its Role in I


Article

The Journal of Physical Chemistry B (39) Niles, J. C.; Wishnok, J. S.; Tannenbaum, S. R. Spiroiminodihydantoin Is the Major Product of the 8-Oxo-7, 8-Dihydroguanosine Reaction with Peroxynitrite in the Presence of Thiols and Guanosine Photooxidation by Methylene Blue. Org. Lett. 2001, 3, 963−966. (40) Niles, J. C.; Wishnok, J. S.; Tannenbaum, S. R. PeroxynitriteInduced Oxidation and Nitration Products of Guanine and 8Oxoguanine: Structures and Mechanisms of Product Formation. Nitric Oxide 2006, 14, 109−121. (41) Bhattacharjee, K.; Mishra, P. C.; Shukla, P. K. Mechanism of Methylation of 8-Oxoguanine Due to Its Reaction with Methyldiazonium Ion. Mol. Simul. 2017, 43, 196−204. (42) Lee, J. M.; Niles, J. C.; Wishnok, J. S.; Tannenbaum, S. R. Peroxynitrite Reacts with 8-Nitropurines to Yield 8-Oxopurines. Chem. Res. Toxicol. 2002, 15, 7−14. (43) Ahmed, K. A.; Sawa, T.; Akaike, T. Protein Cysteine SGuanylation and Electrophilic Signal Transduction by Endogenous Nitro-Nucleotides. Amino Acids 2011, 41, 123−130. (44) Akaike, T.; Ihara, H.; Sawa, T. 8-Sh-Cgmp Endogenously Formed from 8-Nitro-Cgmp as a Second Messenger of Hydrogen Sulfide. Nitric Oxide 2012, 27, S14−S15. (45) Cadet, J.; Delatour, T.; Douki, T.; Gasparutto, D.; Pouget, J.-P.; Ravanat, J.-L.; Sauvaigo, S. Hydroxyl Radicals and DNA Base Damage. Mutat. Res. 1999, 424, 9−21. (46) Steenken, S. Purine Bases, Nucleosides, and Nucleotides: Aqueous Solution Redox Chemistry and Transformation Reactions of Their Radical Cations and E- and Oh Adducts. Chem. Rev. 1989, 89, 503−520. (47) Zhao, Y.; Truhlar, D. G. The M06 Suite of Density Functionals for Main Group Thermochemistry, Thermochemical Kinetics, Noncovalent Interactions, Excited States, and Transition Elements: Two New Functionals and Systematic Testing of Four M06-Class Functionals and 12 Other Functionals. Theor. Chem. Acc. 2008, 120, 215−241. (48) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A., et al. Gaussian 09, revision D.01; Gaussian, Inc.: Wallingford, CT, 2013. (49) Neese, F. The Orca Program System. Wiley Interdiscip. Rev.: Comput. Mol. Sci. 2012, 2, 73−78. (50) Liakos, D. G.; Neese, F. Is It Possible to Obtain Coupled Cluster Quality Energies at near Density Functional Theory Cost? Domain-Based Local Pair Natural Orbital Coupled Cluster Vs Modern Density Functional Theory. J. Chem. Theory Comput. 2015, 11, 4054− 4063. (51) Liakos, D. G.; Sparta, M.; Kesharwani, M. K.; Martin, J. M.; Neese, F. Exploring the Accuracy Limits of Local Pair Natural Orbital Coupled-Cluster Theory. J. Chem. Theory Comput. 2015, 11, 1525− 1539. (52) Riplinger, C.; Neese, F. An Efficient and near Linear Scaling Pair Natural Orbital Based Local Coupled Cluster Method. J. Chem. Phys. 2013, 138, No. 034106. (53) Riplinger, C.; Pinski, P.; Becker, U.; Valeev, E. F.; Neese, F. Sparse Maps-a Systematic Infrastructure for Reduced-Scaling Electronic Structure Methods. Ii. Linear Scaling Domain Based Pair Natural Orbital Coupled Cluster Theory. J. Chem. Phys. 2016, 144, No. 024109. (54) Riplinger, C.; Sandhoefer, B.; Hansen, A.; Neese, F. Natural Triple Excitations in Local Coupled Cluster Calculations with Pair Natural Orbitals. J. Chem. Phys. 2013, 139, No. 134101. (55) Saitow, M.; Becker, U.; Riplinger, C.; Valeev, E. F.; Neese, F. A New near-Linear Scaling, Efficient and Accurate, Open-Shell DomainBased Local Pair Natural Orbital Coupled Cluster Singles and Doubles Theory. J. Chem. Phys. 2017, 146, No. 164105. (56) Mardirossian, N.; Head-Gordon, M. How Accurate Are the Minnesota Density Functionals for Noncovalent Interactions, Isomerization Energies, Thermochemistry, and Barrier Heights Involving Molecules Composed of Main-Group Elements? J. Chem. Theory Comput. 2016, 12, 4303−4325.

(57) Walker, M.; Harvey, A. J.; Sen, A.; Dessent, C. E. Performance of M06, M06-2x, and M06-Hf Density Functionals for Conformationally Flexible Anionic Clusters: M06 Functionals Perform Better Than B3lyp for a Model System with Dispersion and Ionic HydrogenBonding Interactions. J. Phys. Chem. A 2013, 117, 12590−12600. (58) Li, X.; Liao, T.; Chung, L. W. Computational Prediction of Excited-State Carbon Tunneling in the Two Steps of Triplet Zimmerman Di-Π-Methane Rearrangement. J. Am. Chem. Soc. 2017, 139, 16438−16441. (59) Zhao, Y.; Truhlar, D. G. Density Functionals with Broad Applicability in Chemistry. Acc. Chem. Res. 2008, 41, 157−167. (60) Barone, V.; Cossi, M. Quantum Calculation of Molecular Energies and Energy Gradients in Solution by a Conductor Solvent Model. J. Phys. Chem. A 1998, 102, 1995−2001. (61) Cossi, M.; Rega, N.; Scalmani, G.; Barone, V. Energies, Structures, and Electronic Properties of Molecules in Solution with the C-Pcm Solvation Model. J. Comput. Chem. 2003, 24, 669−681. (62) Dennington, R.; Keith, T.; Millam, J. Gaussview, version 5; Semichem Inc.: Shawnee Mission, KS, 2009. (63) Culp, S. J.; Cho, B. P.; Kadlubar, F. F.; Evans, F. E. Structural and Conformational Analyses of 8-Hydroxy-2′-Deoxyguanosine. Chem. Res. Toxicol. 1989, 2, 416−422.

J


OH Radical - ACS Publications

Recommend Documents