Repair Activity of trans-Resveratrol toward 2'-Deoxyguanosine Radicals

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B: Biophysical Chemistry and Biomolecules

Repair Activity of trans-Resveratrol toward 2'-Deoxyguanosine Radicals Xing Cheng, Ping An, Shujin Li, and Liping Zhou J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.7b12100 • Publication Date (Web): 04 Apr 2018 Downloaded from http://pubs.acs.org on April 4, 2018

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The Journal of Physical Chemistry

Repair Activity of trans-Resveratrol toward 2'-Deoxyguanosine Radicals Xing Cheng, Ping An, Shujin Li*, †, Liping Zhou‡ †

College of Chemistry, Chemical Engineering and Materials Science, Soochow University, 215123, PR China

‡

College of Physics, Optoelectronics and Energy, Soochow University, Suzhou, 215006, PR China

ABSTRACT: In the present study, the repair activity of trans-resveratrol toward 2'-deoxyguanosine (dGuo) radicals in polar and non-polar solvents was studied using density functional theory. The hydrogen transfer (HT)/proton coupled electron transfer (PCET) and single electron transfer (SET) mechanisms between trans-resveratrol and dGuo-radicals were considered. Taking into consideration the molar fraction of neutral trans-resveratrol (ROH) and anionic trans-resveratrol (RO-), the overall rate constants for repairing dGuo-radicals by trans-resveratrol are 9.94×108 and 2.01×109 dm3 mol-1 s-1 in polar and non-polar solvents, respectively, and the overall rate constant of repairing cation radical (dGuo+•) by trans-resveratrol via a SET mechanism is 7.17×109 dm3 mol-1 s-1. The repair activity of ROtoward dGuo-radicals is better than that of ROH, but the repair activity of ROH toward dGuo+• is better than that of RO-. Unfortunately, neither ROH nor RO- can repair the 2'-deoxyribose radicals of dGuo. It can therefore be concluded that trans-resveratrol is an effective antioxidant for repairing base radicals of dGuo and dGuo+•. The study can help us understand the repair activity of trans-resveratrol toward 2'-deoxyguanosine radicals.

1 Environment ACS Paragon Plus

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1. Introduction It is well-known that ionizing radiation and reactive oxygen species can damage DNA. The exposure of double-stranded DNA to ionizing radiation leads to the formation of the guanine cation radical (G+•) as guanine has the lowest oxidation potential among all DNA bases.1-4 Since the pKa value of G+• is 3.9,5 it undergoes deprotonation to yield guanyl radicals in physiological conditions (pH=7.4). The excited states of guanine cation radicals in DNA can induce hole transfer to the sugar moiety, which on deprotonation results in neutral sugar radicals.6,7 The reaction of the hydroxyl radical (OH•) with guanine in an aqueous environment has been investigated by previous studies.8-10 It has been shown that the main reaction is the addition of •OH to a C4=C5 double bond and that the adduct radicals (G-OH•) have only a small barrier to the formation of an ion-pair (G+•-OH-), which undergoes deprotonation to form neutral radical G(-H)N1•, G(-H)N2• and H2O. These DNA radicals have high reactivity, and they are related to certain lethal diseases such as Alzheimer’s disease, Parkinson’s disease and heart disease. Over the past few years, biologists have realized that DNA repair is one of the most fundamental processes of life. Amino acids have been reported to be able to repair guanine radicals.11-13 Cysteine, methionine, tyrosine and particularly tryptophan derivatives can repair guanine radicals in plasmid DNA with rate constants of ~105, 105, 106 and 107 dm3 mol-1 s-1, respectively.11 Using density function theory (DFT), Jena et al. found that guanine radicals can be repaired by cysteine and tyrosine through a hydrogen transfer (HT) mechanism.12 Glutathione was found to repair 2'-deoxyribose radicals via an HT mechanism with diffusion-limited rate constants.13 However, amino acid radicals may form DNA-protein cross-links and a potentially large number of reactions may subsequently occur within the protein.14


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A natural polyphenolic compound, trans-resveratrol (trans-3,5,4'-trihydroxystilbene), is present in many plant species such as grapes and peanuts. It has a surprising number of health benefits, especially for the mitigation of age-related diseases, including neurodegeneration, carcinogenesis

and

atherosclerosis,15

and

experimental

results

have

indicated

that

trans-resveratrol has an anticarcinogenic effect on several kinds of cancer, including prostate, breast and skin cancers.16-19 Recently, trans-resveratrol was found to prolong the lifespan of diabetic mice20-23 and to possess a variety of biological activities, especially the in vivo scavenging of free radicals due to its 4'-hydroxyl group.24-27 More importantly, the trans-resveratrol radical has a semiquinone structure that is very stable and does not react with DNA or protein. The strong affinity of trans-resveratrol for cell walls also makes it a very efficient repair substance.28 Iuga et al. studied the reaction of trans-resveratrol with •OH and •OOH radicals in an aqueous phase using DFT.25 They reported that the HT from the OH group in ring B to •OH and •OOH radicals was more favorable than from the OHs in ring A due to the resonance effects of the trans-resveratrol radical product. Bond dissociation energies and ionization potentials for trans-resveratrol have been estimated in both a gas phase and in an aqueous solution.28-30 It has been found that its bond dissociation energies were lower than its ionization potentials. The repair activities of silybin,31 hydroxycinnamic acid derivatives,32 quercetin and rutin33 towards dGMP hydroxyl adduct radicals have also been investigated experimentally. It has been shown that polyphenols have high reactivity toward DNA adduct radicals with approximate diffusion controlled rates of 108~109 dm3 mol-1 s-1. Natural polyphenols, a class of powerful electron and/or hydrogen donating antioxidants, are considered as important substances for effectively scavenging DNA radicals. However, theoretical studies of the repair activity of polyphenol



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compounds on damaged DNA radicals have not yet been reported. Moreover, it is difficult to capture and detect these products during their repair processes through experimental methods, so theoretical studies are necessary for this field. In this study, we have carried out a systematic investigation of the repair activity of trans-resveratrol toward 2'-deoxyguanosine (dGuo) radicals using DFT and computational kinetics methods. We considered HT/proton coupled electron transfer (PCET) and single electron transfer (SET) mechanisms. We also considered the influence of solvent polarity and of the acid-base equilibrium of trans-resveratrol in aqueous solution on the repair mechanisms. 2. Computational details In the present study, the Gaussian 09 program34 was used for all electronic structure calculations. For the HT/PCET mechanism, full geometry optimizations and frequency calculations were carried out in a gas phase for all stationary points using the M06-2X35 functional with the basis set 6-311G(d,p) and an ultrafine grid. To treat solvent effect on the calculated Gibbs free energies, single point energy calculations were performed at the M06-2X/ma-TZVP36,37 level using the optimized geometries for the corresponding gas phase and the SMD continuum model,38 with water and benzene as solvents to mimic polar and non-polar environments, respectively. The local potential minima and transition state were confirmed by analyzing the number of imaginary frequencies (NIMAG=0 or 1). Transition state structure was verified to connect the reactants to products with the help of intrinsic reaction coordinate (IRC) calculations39 at the M06-2X/6-311G(d,p) level. Gibbs free energy Gsol was obtained in aqueous or benzene media with the following equation: Gsol= EHF + G0, where EHF represents the total calculated

electronic

energy

in

aqueous

or


benzene

media

at

the

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M06-2X/ma-TZVP//6-311G(d,p) level, and G0 is the thermal correction to Gibbs free energy in the gas phase. The method used for Gibbs free energy in both aqueous and benzene media for this study was the same as that used in the literature.40-42 Gibbs free energy barrier (∆G≠) was calculated as the difference of Gsol between the transition state and reactants, and Gibbs free energy of reaction (∆G) was calculated as the difference of Gsol between products and reactants. The rate constants (kTST) at 1 mol dm-3 standard state can be obtained by conventional transition state theory (TST)43-45 as in the following formula (1): ≠

G k B T − ∆RT k TST =σκ e h

(1)

where ∆G≠ is the Gibbs free energy barrier, κ accounts for the tunneling corrections that were calculated using the zero curvature tunneling (ZCT) method and the Eckart barrier.46 σ represents the reaction path degeneracy accounting for the number of equivalent reaction paths. kB and h are the Boltzman and Plank constants, respectively. Marcus theory was used to obtain the ∆G≠ for the SET mechanism.47-48 Single point energy was calculated at the M06-2X/ma-TZVP level using the corresponding optimized structure at the M06-2X/6-311G(d,p) level for the aqueous media. ∆G≠ was defined in terms of ∆G and nuclear reorganization energy (λ):

λ  ∆G  ∆G = 1+  4 λ  ≠

2

(2)

A very simple approximation can be used to calculate λ: λ≈∆E-∆G, where ∆E is the nonadiabatic energy difference between reactants and vertical products.



In the case of a rate constant close to the diffusion-limit, the rate constants could not be directly obtained using TST calculations. The apparent rate constants (k) were calculated using Collins-Kimball theory49 as in the following formula:

k=

kD kTST kD +kTST

(3)

where kTST is the thermal rate constant obtained by using TST calculations (eq 1), and kD is the steady-state Smoluchowski50 rate constant for an irreversible bimolecular diffusion-controlled reaction. This was calculated along with the following formula:

kD =4πRAB DAB N A

(4)

where RAB denotes the reaction distance. The following criteria was used to estimate RAB51: for the HT mechanism, RAB was taken from the transition state as the distance between the two atoms that were involved in the H transfer; for the SET mechanism, RAB was the sum of the radius of the reactants. NA was the Avogadro number, and DAB was the mutual diffusion coefficient of the reactants A (free radicals) and B (trans-resveratrol). DAB was calculated from DA and DB according to ref 52, and DA and DB were estimated using the Stokes-Einstein approach:53,54

DA or B =

kB T 6πηaA or B

(5)

where η denotes the viscosity of the solvent, for example, water (η=8.91×10-4 Pa s ) or benzene (η=6.04×10-4 Pa s ), and a is the radius of the solute that was calculated using a Multiwfn software package.55 kB is the Boltzmann constant and T is temperature. The values of RAB, DAB, kD and a are listed in Tables S1 to S3 of this study (Supporting Information).


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3. Results and discussion The first pKa value of trans-resveratrol is 8.8,56 which means that the molar fractions of the neutral (ROH) and anionic (RO-) forms of trans-resveratrol are 0.962 and 0.038 in physiological conditions (pH=7.4), respectively, as shown in Figure S1 (Supporting Information). Their relative population shows that ROH is the dominant species in physiological conditions. However, if RO- reacts quickly enough with radicals, the contribution of RO- to the repair activity of trans-resveratrol cannot be ignored. It has been reported that the repair activity of polyphenol anion is better than that of corresponding neutral polyphenol for the SET mechanism.57,58 Accordingly, the repair activity of both ROH and RO- towards dGuo-radicals was studied. The structures of ROH and RO- are shown in Figure 1(a) and (b), respectively. Since deprotonation from trans-resveratrol in a non-polar solvent is impossible, RO- was only considered in an aqueous solution. Eight radicals of dGuo that are repaired by trans-resveratrol were analyzed in this study. The first three were the base radicals of dGuo, denoted as dGuo(-H)N1•, dGuo(-H)N2a• and dGuo(-H)N2b•, which are formed by the abstraction of a hydrogen atom from the N1 site and from the exocyclic NH2 of the base moiety. The abstraction of a hydrogen atom from the C8 site is highly improbable,59 and its repair by trans-resveratrol was not considered. Number four to seven are 2'-deoxyribose radicals of dGuo, denoted as dGuo(-H)C1'•, dGuo(-H)C3'•, dGuo(-H)C4'• and dGuo(-H)C5'•, which are formed by the abstraction of a hydrogen atom from the C1', C3', C4' and C5' sites as shown in Figure 1 (c). These carbon-centered radicals may exist in DNA.60-62 The last one was the dGuo cation radical, denoted as dGuo+•.



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2' 3' 2' 3' HO HO 1' 4' 1' 4' 6 6 OH O 5 B 5 B 1 1 4 A 4 A 6' 5' 6' 5' 3 3 2 2 HO HO (a) ROH (b) RO O 7 1 5 N HN 6 9 8 Ha N 5' OH N 2 N 4 O 3 4' Hb 1' 3' 2' OH (c) dGuo

Figure 1. (a) Neutral form of trans-resveratrol (ROH), (b) anionic form of trans-resveratrol (RO-) and (c) 2'-deoxyguanosine (dGuo). The reactions considered for repairing the dGuo-radicals and dGuo+• by trans-resveratrol were as follows: (1) The hydrogen atom transfer from the 4'-OH of ROH to the dGuo-radicals (HT mechanism) ROH + dGuo(-H)• → RO• + dGuo

(HT mechanism)

(a1) HT from ROH to dGuo(-H)N1• (a2) HT from ROH to dGuo(-H)N2a• (a3) HT from ROH to dGuo(-H)N2b• (a4) HT from ROH to dGuo(-H)C1'• (a5) HT from ROH to dGuo(-H)C3'• (a6) HT from ROH to dGuo(-H)C4'•


(a)

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(a7) HT from ROH to dGuo(-H)C5'• (2) The hydrogen atom transfer from the 5'-OH of RO- to the dGuo-radicals (HT mechanism) or the proton coupled electron transfer from the 5'-OH of RO- to the dGuo-radicals (PCET mechanism) RO- + dGuo(-H)• → RO (-H)-• + dGuo

(HT/PCET mechanism)

(b)

(b1) PCET from RO- to dGuo(-H)N1• (b2) PCET from RO- to dGuo(-H)N2a• (b3) PCET from RO- to dGuo(-H)N2b• (b4) HT from RO- to dGuo(-H)C1'• (b5) HT from RO- to dGuo(-H)C3'• (b6) HT from RO- to dGuo(-H)C4'• (b7) HT from RO- to dGuo(-H)C5'• (3) The single electron transfer from ROH to the dGuo-radicals and dGuo+• (SET mechanism) ROH + dGuo(-H)• → ROH+•+ dGuo(-H)-

(SET mechanism)

(c1) SET from ROH to dGuo(-H)N1• (c2) SET from ROH to dGuo(-H)N2a• (c3) SET from ROH to dGuo(-H)N2b•


(c)


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(c4) SET from ROH to dGuo(-H)C1'• (c5) SET from ROH to dGuo(-H)C3'• (c6) SET from ROH to dGuo(-H)C4'• (c7) SET from ROH to dGuo(-H)C5'• (c8) SET from ROH to dGuo+• (4) The single electron transfer from RO- to the dGuo-radicals and dGuo+• (SET mechanism) RO- + dGuo(-H)• → RO• + dGuo(-H)- (SET mechanism)

(d)

(d1) SET from RO- to dGuo(-H)N1• (d2) SET from RO- to dGuo(-H)N2a• (d3) SET from RO- to dGuo(-H)N2b• (d4) SET from RO- to dGuo(-H)C1'• (d5) SET from RO- to dGuo(-H)C3'• (d6) SET from RO- to dGuo(-H)C4'• (d7) SET from RO- to dGuo(-H)C5'• (d8) SET from RO- to dGuo+• It should be noted that the SET mechanism (c1 to c7 and d1 to d7) must be followed by the protonation of the formed dGuo anion for the restoration of the original structure of dGuo.


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3.1 The Repair Activity of ROH and RO- toward dGuo-Radicals via an HT Mechanism. The repair activity of ROH toward dGuo-radicals via HT mechanism was studied in both polar and non-polar solvents; however, since deprotonation of trans-resveratrol in a non-polar solvent is impossible, RO- was only considered in an aqueous solution. The HT mechanism from ROH to the dGuo-radicals was modeled with the hydrogen atom being transferred from 4'-OH because 4'-OH is the most reactive site due to the resonance effects that have been demonstrated by previous studies.24-27 The HT mechanism from RO- to the dGuo-radicals was modeled with the hydrogen atom being transferred from 5-OH as the difference between the 3-OH and 5-OH of trans-resveratrol is relatively small for HT mechanism.25 The ∆G, ∆G≠ and rate constants at 298.15K of reactions a1 to a7 and b1 to b7 are listed in Tables 1 and 2, respectively. 3.1.1 The repair activity of ROH toward dGuo-radicals via an HT mechanism. For repair reactions a1 to a3, the optimized transition state structures for the gas phase at the M06-2X/6-311G(d,p) level are shown in Figure 2. The OROH···HROH and NdGuo···HROH distances in the transition states were in the range of 1.206~1.294Å and 1.179~1.269Å, respectively. The imaginary vibrational frequencies at the transition states fell in the range of 2613~3686 cm-1. The vibrational mode corresponding to the imaginary frequency at the transition states indicates that this vibration was essentially the characteristic H atom motion between the OROH and NdGuo atoms.



Figure 2. Optimized transition state structures of reactions a1 to a3 in the gas phase at the M06-2X/6-311G(d,p) level. For repair reactions a4 to a7, the optimized transition state structures for the gas phase at M06-2X/6-311G(d,p) level are shown in Figure S2 and the Cartesian coordinates of the optimized transition state structures of reactions a1 to a7 are listed in Table S4 (Supporting Information). The OROH···HROH and C'dGuo···HROH distances at the transition states were in the range of 1.194~1.266Å and 1.285~1.340Å, respectively. The imaginary vibrational frequencies at the transition states were found to fall in the range of 1848~1963 cm-1. From Table 1, it can be seen that all repair reactions of dGuo-radicals by ROH were predicted to be exergonic. The ∆G values were in the range of -11.86~-5.79 kcal mol-1 in polar solvent and were in the range of -13.85~-8.98 kcal mol-1 in non-polar solvent.


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Table 1. Gibbs free energies ∆G and Gibbs free energy barriers ∆G≠ (kcal mol-1) at the M06-2X/ma-TZVP//6-311G(d,p) level and apparent rate constants k (dm3 mol-1 s-1) at 298.15K for ROH via an HT mechanism in water and benzene phases Water Benzene reactions ∆G ∆G≠ k ∆G ∆G≠ k 4 a1 -7.99 14.34 1.36×10 -12.38 6.47 1.46×109 a2 -11.04 12.24 2.63×106 -10.39 8.86 5.45×108 3 a3 -11.86 14.90 2.04×10 -13.85 11.09 1.26×106 a4 -7.31 24.21 negligiblea -8.98 18.66 1.76×102 a a5 -7.18 26.71 negligible -10.61 20.38 1.68×101 a a6 -5.79 30.27 negligible -9.58 22.40 1.39 a7 -8.25 24.29 negligiblea -11.77 19.60 1.04×102 a k < 1 dm3 mol-1 s-1

In polar solvent, the ∆G≠ of reactions a1 to a3 were in the range of 12.24 to 14.90 kcal mol-1, and reaction a2 had the lowest barrier. The reaction barriers of a1 to a3 in non-polar solvent were found to be systematically lower than those in polar solvent by 4~8 kcal mol-1, and reaction a1 had the lowest barrier in non-polar solvent. The ∆G≠ of reactions a4 to a7 were much higher than those of reactions a1 to a3. The ∆G≠ values of reactions a4 to a7 were in the range of 24.21 to 30.27 kcal mol-1 in polar solvent and were in the range of 18.66 to 22.40 kcal mol-1 in non-polar solvent. The ∆G≠ values of polar solvent were higher than those of non-polar solvent. The rate constants (k) were calculated at 298.15 K as listed in Table 1. The tunneling corrections (κ), reaction path degeneracies (σ) and rate constant kTST,water of the water phase and kTST,benzene of the benzene phase that were obtained from the TST calculations of reactions a1 to a7 are listed in Tables S5 and S6 (Supporting Information), respectively. In Table 1, the rate constants (k) of reactions a1 to a3 are much greater than those of reactions a4 to a7, which are in good agreement with the ∆G≠ as discussed above. ROH preferentially repaired dGuo(-H)N2a• radicals via an HT mechanism with a rate constant of 2.63×106 dm3 mol-1 s-1 in polar solvent. The rate constants of repairing dGuo(-H)N1•, dGuo(-H)N2a• and dGuo(-H)N2b• by ROH were



1.46×109, 5.45×108 and 1.26×106 dm3 mol-1 s-1 in non-polar solvent, respectively. These results show that the repair activity of ROH on base radicals in non-polar solvent is better than that of polar solvent. The rate constants of reactions a4 to a7 were relatively small for both polar and non-polar solvents, which indicates that ROH cannot repair 2'-deoxyribose radicals of dGuo via an HT mechanism. Therefore, only the base radicals of dGuo could be repaired to a significant extent. Moreover, according to the results from the present work, the HT from ROH to radicals N1, N2a and N2b were predicted as efficient pathways for repairing dGuo-radicals. 3.1.2 The repair activity of RO- toward dGuo-radicals via an HT/PCET mechanism. Repair reactions b1 to b3 were clearly barrierless. The ∆G diagram for repair reactions b1 to b3 is shown in Figure 3. The optimized structures of the reactant complexes (RC) of reactions b1 to b3 and intermediates (IM) of reactions b1 and b2 are shown in Figure S3, and their Cartesian coordinates are listed in Table S6 (Supporting Information). The intermediate of reaction b1 or b2 had an imaginary frequency of which the vibrational mode was essentially the characteristic hydrogen motion between the ORO- and NdGuo atoms. As shown in Figure 3, the ∆G of reactions b1 to b3 decreased until the H atom of 5-OH in ring A of RO- was completely transferred to the base radicals and products were formed. The reactions b1 to b3 were strictly diffusion-controlled due to being barrierless. We noticed that when dGuo(-H)N1•, dGuo(-H)N2a• and dGuo(-H)N2b• radicals were close to the H atom of 5-OH in ring A of RO- forming reactant complexes (denoted as RC-N1, RC-N2a and RC-N2b). The total charge of RO- and the base radicals in reactant complexes were -0.2 and -0.8, respectively, so reactions b1 to b3 may be through a PCET mechanism rather than an HT mechanism.


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Despite our best efforts, we failed to locate the IM of reaction b3. Based on the results of reactions b1 and b2, we believe that repair reaction b3 was also strictly diffusion-controlled.

Figure 3. The Gibbs free energy diagram of reactions b1 to b3. For repair reactions b4 to b7, the optimized transition state structures are shown in Figure S4, and their Cartesian coordinates are listed in Table S8 (Supporting Information). The ORO-···HRO- and C'dGuo···HRO- distances at transition states were in the range of 1.040 to 1.253Å and 1.288 to 1.713Å, respectively. The imaginary vibrational frequencies at transition states were found to lie in the range of 1916 to 3236 cm-1. As shown in Table 2, repair reactions b4 to b7 were favored in terms of ∆G, but their ∆G≠ were in the range of 24.25 to 34.09 kcal mol-1. Repair reactions b1 to b3 were diffusion-controlled. Their rate constants in polar solvent were in the order of 109 dm3 mol-1 s-1. The rate constants for reactions b4 to b7 were lower than 1 dm3 mol-1 s-1. Accordingly, RO- did not repair 2'-deoxyribose radicals of dGuo via an HT mechanism.



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Table 2. Gibbs free energies ∆G and Gibbs free energy barriers ∆G≠ (kcal mol-1) at M06-2X/ma-TZVP//6-311G(d,p) level and apparent rate constants k (dm3 mol-1 s-1) at 298.15K for RO- via an HT/PCET mechanism in a water phase reactions ∆G ∆G≠ k b1 -6.46 1.21×109 b2 -9.50 1.22×109 b3 -10.33 ~1.21×109 b4 -5.77 26.01 negligiblea b5 -5.64 24.25 negligiblea b6 -4.26 34.09 negligiblea b7 -6.71 28.55 negligiblea a k < 1 dm3 mol-1 s-1

Therefore, it seems valid to state that, via an HT/PCET mechanism, both ROH and RO- can repair base radicals rather than the 2'-deoxyribose radicals of dGuo. Reactions a1 to a3 most easily occurred in non-polar solvent, and their rate constants were in the range of 1.26×106 to 1.46×109 dm3 mol-1 s-1. However, their rate constants in polar solvent were in the range of 2.04×103 to 2.63×106 dm3 mol-1 s-1. Reactions b1 to b3 were barrierless and their rate constants were diffusion-controlled. Therefore, with an HT/PCET mechanism, the repair activity of ROtoward the base radicals of dGuo was better than that of ROH toward the same. 3.2 The Repair Activity of ROH and RO- toward dGuo-Radicals and dGuo+• via a Single Electron Transfer (SET) Mechanism. The SET mechanism was only considered in aqueous

solution.

The

M06-2X/ma-TZVP36,37

single level

point

using

energy a

calculations

corresponding

were

optimized

performed

at

the

structure

at

the

M06-2X/6-311G(d,p) level in aqueous media and using an SMD continuum model.38


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Table 3. Gibbs free energies ∆G and Gibbs free energy barriers ∆G≠ at M06-2X/ma-TZVP//6-311G(d,p) level, nuclear reorganization energy λ, (kcal mol-1) and apparent rate constants k (dm3 mol-1 s-1) for ROH and RO- via a SET mechanism in a water phase at 298.15K reactions ∆G ∆G≠ λ k c1 8.07 8.46 12.49 3.91×106 15.15 48.8 c2 14.51 9.54 15.84 15.2 c3 15.01 9.44 78.45 negligiblea c4 59.74 20.54 94.47 negligiblea c5 67.79 20.74 78.59 negligiblea c6 58.87 19.57 77.72 negligiblea c7 61.22 22.61 0.90 7.45×109 c8 -5.57 12.19 0.26 7.45×109 d1 -13.69 10.38 0.00 7.46×109 d2 -7.26 7.44 0.01 7.45×109 d3 -6.75 7.33 43.16 negligiblea d4 37.98 18.44 56.09 negligiblea d5 46.03 18.63 42.63 negligiblea d6 37.11 17.46 43.85 negligiblea d7 39.46 20.50 7.37 2.46×107 d8 -27.33 10.09 a 3 -1 -1 k < 1 dm mol s

3.2.1 The repair activity of ROH toward dGuo-radicals and dGuo+• via a SET mechanism. Repair reactions c1 to c7 were found to be significantly endergonic (Table 3). The ∆G values for repairing base radicals of dGuo (c1 to c3) were lower than those for repairing 2'-deoxyribose radicals of dGuo (c4 to c7). The ∆G≠ values for reactions c1 to c3 ranged from 8.46 to 15.84 kcal mol-1, which indicates that these reactions may take place at significant rates. The repairing of dGuo(-H)N1• (c1) involved the lowest barrier among the repairing of the base radicals of dGuo (c1 to c3). However, the ∆G≠ values for reactions c4 to c7 ranged from 77.72 to 94.47 kcal mol-1, which indicates that the repair of 2'-deoxyribose radicals of dGuo by ROH is not easy. Alvarez-Idaboy et al. reported that glutathione monoanion (GSH-) was unlikely to repair 2'-deoxyribose radicals of dGuo through a SET mechanism because GSH- is a poor electron donor, but they predicted that polyphenols might be capable of doing so.13 However,



according to our results, ROH could not repair 2'-deoxyribose radicals of dGuo via a SET mechanism. The vertical ionization potential (AqVIP), adiabatic ionization potential (AqAIP), vertical electron affinities (AqVEA) and adiabatic electron affinities (AqAEA) of the studied species in aqueous solution at the M06-2X/ma-TZVP//6-311G(d,p) level are listed in Table 4. It is shown that the values of AqAIP decreased and the values of AqAEA increased as compared to the vertical values.

Table 4. The vertical electron affinities AqVEA (eV), adiabatic electron affinities AqAEA (eV), vertical ionization potential AqVIP (eV) and adiabatic ionization potential AqAIP (eV) of the studied species in water phase at the M06-2X/ma-TZVP//6-311G(d,p) level Aq Aq Aq Aq Species VEA AEA Species VIP AIP dGuo(-H)N1• 4.832 5.166 ROH 5.723 5.539 dGuo(-H)N2a• 4.680 4.896 RO4.688 4.597 dGuo(-H)N2b• 4.663 4.880 Phenol 6.344(6.300)a 6.126 dGuo(-H)C1'• 2.242 (2.081)a 2.963 phenol anion 4.868(4.860)a 4.772 a a dGuo(-H)C3'• 1.884 (1.844) 2.666 GSH 7.003(6.986) 6.445 dGuo(-H)C4'• 2.322 (2.172)a 3.060 GS24.568(4.575)a 4.491 a dGuo(-H)C5'• 2.088 (1.992) 2.890 dGuo+• 5.436(5.788)a 5.769 a Values in parentheses are from ref 13 calculated at M05-2X/6-31+G(d,p) level.

Vertical ionization potential (AqVIP) and the adiabatic ionization potential (AqAIP) were calculated according to the following formulas:13,63

Aq

VIP=EN-1 ( g N )aq -EN ( g N )aq

and

Aq

' AIP=EN-1 ( g N-1 )aq -EN ( g N )aq

where EN (gN)aq is the energy of the N electron system calculated at geometry gN, optimized in aqueous solution, EN-1(gN)aq is the energy of the (N-1) electron system calculated at geometry gN, and E'N-1 (gN-1)aq is the energy of the (N-1) electron system calculated at geometry gN-1, optimized in aqueous solution.


Page 18 of 45

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In aqueous solution, the energetic cost of removing one electron from ROH (vertical ionization potential in aqueous solution, Aq

Aq

VIP) was estimated to be 5.723eV (Table 4). The

VIP of ROH was relatively low compared to phenol and glutathione monoanion (GSH-). It was

lower than that of phenol (AqVIP (phenol)=6.344 eV) by 0.621eV and lower than that of glutathione monoanion (AqVIP(GSH-)=7.003eV calculated at the M06-2X/ma-TZVP//6-311G(d,p) level in this study)

by

1.280eV.

As

shown

in

Table

4,

the

Aq

VIP

values

at

the

M06-2X/ma-TZVP//6-311G(d,p) level in our study were in good agreement with previously shown results at the M05-2X/6-31+G(d,p) level, which evaluated the reliability of their results.13 The AqVIP of ROH was 5.723eV, which indicates that ROH is a good electron donor. However, as the values shown in Table 3 demonstrate, ROH may repair base radicals rather than 2'-deoxyribose radicals of dGuo via a SET mechanism. This indicates that electron accepting capacity of dGuo-radicals varies drastically. To illustrate this issue, the vertical electron affinities (AqVEA) and adiabatic electron affinities (AqAEA) of dGuo-radicals in aqueous solution were calculated according to the following formulas:13,64 Aq

VEA=E N ( g N )aq -E N+1 ( g N )aq

and

Aq

' AEA=EN ( g N )aq -EN+1 ( g N+1 )aq

where EN+1 (gN)aq is the energy of the (N+1) electron system calculated at geometry gN, ' optimized in aqueous solution, and EN+1 (gN+1)aq is the energy of the (N+1) electron system

calculated at geometry gN+1. The

Aq

VEA values of the 2'-deoxyribose radicals of dGuo were very low (~2eV), so

2'-deoxyribose radicals of dGuo were not repaired by ROH via a SET mechanism. However, for the base radicals of dGuo, the AqVEA values were relatively high and were in the range of 4.663 to 4.832 eV. Therefore, the electron acceptor capability of the base radicals of dGuo was higher



Page 20 of 45

than that of the 2'-deoxyribose radicals of dGuo. ROH may repair base radicals of dGuo via a SET mechanism because the

Aq

VIP value of ROH was relatively low and the

Aq

VEA values of

base radicals were high. As has been demonstrated, GSH- cannot repair dGuo(-H)N1• via a SET mechanism because the AqVIP value of GSH- is relativity high.13 Repair reaction c8 on the cation radical (dGuo+•) by ROH via a SET mechanism was exergonic (Table 3), and the ∆G was -5.57 kcal mol-1. The ∆G≠ was 0.90 kcal mol-1. The dGuo+• could be repaired by ROH via a SET mechanism due to the higher

Aq

VEA value (5.436eV) of

dGuo+•. The rate constants for repair reactions on c1 to c3 by ROH via SET mechanisms were in the range of 15.2 to 3.91×106 dm3 mol-1 s-1. The rate constants for repairing 2'-deoxyribose radicals of dGuo (c4 to c7) were negligible. The rate constant of repairing dGuo+• by ROH (c8) was 7.41×109 dm3 mol-1 s-1. ROH preferentially repairs dGuo+• and dGuo(-H)N1• radicals via a SET mechanism. 3.2.2 The repair activity of RO- toward dGuo-radicals and dGuo+• via a SET mechanism. Even though the population of RO- in physiological conditions (pH=7.4) is considerably lower than that of ROH and the molar fraction of RO- is 0.038, it is a much better electron donor. The

Aq

VIP value of RO- is 4.688 eV (Table 4). This value was lower than those

of ROH and phenol anion by 1.035 and 0.180 eV, respectively, and was higher than that of glutathione dianion (GS2-) by 0.120 eV. The reactions d1 to d3 were predicted to be exergonic (Table 3). ∆G of reactions d1 to d3 were in the range of -13.69 to -6.75 kcal mol-1, and their ∆G≠ values were very low (~ 0 kcal mol-1). The rate constants of reactions d1 to d3 were about 7.5×109 dm3 mol-1 s-1. The reactions d4 to d7 were still found to be endergonic and their ∆G


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values were in the range of 37.11 to 46.03 kcal mol-1 (Table 3). Their ∆G≠ values were in the range of 42.63 to 56.09 kcal mol-1, and they were much higher than those of reactions d1 to d3. RO- is a good electron donor, but 2'-deoxyribose radicals of dGuo cannot be repaired by RO- via a SET mechanism because their electron accepting capacity is poor.

Figure 4. Gibbs free energy barrier ∆G≠ vs Gibbs free energy ∆G. The repairing of dGuo+• (d8) by RO- via a SET mechanism was found to be largely exergonic (∆G=-27.33 kcal mol-1), and its ∆G≠ value was 7.37 kcal mol-1 (Table 3). Although the exergonicity of reaction d8 was larger than that of reaction c8, the ∆G≠ value of reaction d8 was significantly higher than that of reaction c8. This apparently contra-intuitive behavior can be explained based on the fact that reaction d8 is in the inverted region of the Marcus parabola65-68 as shown in Figure 4. The absolute value of the difference between ∆G and -λ of reaction d8 (∣∆G-(-λ)∣=17.24 kcal mol-1) was the largest, which causes the largest increase in ∆G≠ value. The absolute value of the difference between ∆G and -λ of reaction c8 was 6.62 kcal mol-1, which is much smaller than 17.24 kcal mol-1; therefore, the ∆G≠ value of reaction c8 was lower than that of reaction d8. For reactions d1, d2 and d3, the absolute values of the difference between ∆G and -λ were 3.30, 0.18 and 0.58 kcal mol-1, respectively, which lead to relatively



low ∆G≠ values (Table 3 and Figure 4). Therefore, the most exergonic processes do not correspond to the fastest reactions. In fact, the rate constants of reactions c8 and d8 were 7.45×109 and 2.46×107 dm3 mol-1 s-1, respectively. Thus, via a SET mechanism, RO- can repair base radicals rather than the 2'-deoxyribose radicals of dGuo. The rate constants for repairing base radicals of dGuo via a SET mechanism by RO- were several orders of magnitude higher than those of ROH. This shows a good consistency with the previous results that proposed that a SET process was favorable to polyphenol anions rather than neutral polyphenols.57,58 The dGuo+• radical is also repaired by RO- via a SET mechanism. 3.3 The Repair Activity of trans-Resveratrol toward dGuo-Radicals and dGuo+•. In order to evaluate the repair activity of ROH and RO- toward dGuo-radicals and dGuo+•, total rate constants of repairing dGuo-radicals by ROH and RO- in polar solvent and non-polar solvent were calculated as the sum of the apparent rate constants of all reaction paths in each solvent ROH

according to ref 51. For example, the total constants (ktotal ) of repairing dGuo-radicals by ROH in polar solvent were calculated with the following formula: ROH

ROH

ROH

ktotal =kHT +kSET ROH

where kHT

ROH

and kSET are calculated as the sum of the apparent rate constants of all repair

reactions by ROH in polar solvent via HT and SET mechanisms, respectively, as seen in following equations: ROH

kHT

=ka1 + ka2+ ka3 + ka4+ ka5+ ka6+ ka7

and

ROH

kSET = kc1 + kc2+ kc3 + kc4+ kc5+ kc6+ kc7


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ROH

The total rate constant (ktotal ) of repairing dGuo-radicals by ROH in polar and non-polar RO-

solvents, and the total rate constant (ktotal ) in polar solvent are listed in Table 5.

Table 5. The total rate constants of repairing dGuo-radicals and dGuo+• by ROH and RO- (dm3 mol-1 s-1) repairing repairing repairing repairing repairing ROH RO+ dGuo-radicals dGuo • dGuo-radicals dGuo-radicals dGuo+• ROH RO kHT 2.65×106 — 2.01×109 kHT/PCET 3.64×109 — ROH RO 6 9 10 kSET 3.91×10 7.45×10 — kSET 2.24×10 2.46×107 ROH RO ktotal 6.56×106 7.45×109 2.01×109 ktotal 2.60×1010 2.46×107 -

-

-

For repairing dGuo-radicals by ROH and RO- in polar solvent, the total rate constants for k RO-

ROH total

and ktotal were 6.56×106 and 2.60×1010 dm3 mol-1 s-1, respectively. The rate constants for k

ROH HT

and kHT/PCET were 2.65×106 and 3.64×109 dm3 mol-1 s-1, respectively. The rate constants for

RO-

RO-

ROH

kSET and kSET were 3.91×106 and 2.24×1010 dm3 mol-1 s-1, respectively. The repair activity of RO- toward dGuo-radicals was better than that of ROH. The total rate constant for repairing dGuo•+ by ROH and RO- in polar solvent were 7.45×109 and 2.46×107 dm3 mol-1 s-1 respectively, via a SET mechanism. Therefore, the repair activity of ROH toward dGuo+• was better than that of RO-. The overall rate constants k1 and k2 for repairing dGuo-radicals and dGuo+• by trans-resveratrol in polar solvent were defined by the following formula, according to ref 51: ROH

RO-

k1/k2 = fROH× ktotal + fRO-× ktotal where fROH and fRO- are the molar fractions of neutral (ROH) and anionic (RO-) forms of trans-resveratrol in physiological conditions (pH=7.4), respectively.



Table 6. The overall rate constant k1 or k2 (dm3 mol-1 s-1) of repairing dGuo-radicals and dGuo+• by trans-resveratrol at pH=7.4 in aqueous solution at 298.15K ROH RO species fROHa×ktotal fRO- a× ktotal k1 k2 6 8 8 dGuo-radicals 6.31×10 9.88×10 9.94×10 dGuo+• 7.17×109 9.35×105 7.17×109 a fROH=0.962 and fRO =0.038 -

As listed in Table 6, the overall rate constants k1 and k2 are 9.94×108 and 7.17×109 dm3 mol-1 s-1, respectively. Therefore, trans-resveratrol can effectively repair dGuo-radicals and dGuo+• in aqueous solution. In addition, the repair activity of trans-resveratrol in non-polar solvent (2.01×109 dm3 mol-1 s-1, table 5) is slightly better than that of in polar solvent (9.94×108 dm3 mol-1 s-1). The overall rate constant k1 in our study was in good agreement with experiments where the rate constants were about 108~109 dm3 mol-1 s-1 for repairing dGuo-radicals with polyphenols.69,70 Based upon the results of this work as well as that of previous work,69,70 we believe that trans-resveratrol has one of the greatest potentials as an antioxidant in the repair of DNA radicals. 4. Conclusion The repair mechanisms and kinetics on dGuo radicals by ROH and RO- forms of trans-resveratrol in polar and non-polar solvents have been studied using DFT, and HT/PCET and SET mechanisms have been considered. It was found that trans-resveratrol could repair base radicals of dGuo rather than 2'-deoxyribose radicals regardless of the polarity of the environment. The repair activity of ROtoward dGuo-radicals is better than that of ROH. The overall rate constants for repairing dGuo-radicals by trans-resveratrol are 9.94×108 and 2.01×109 dm3 mol-1 s-1 in polar and non-polar solvents, respectively. When the molar fractions of ROH and RO- are considered in a


Page 24 of 45

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polar solvent, the total rate constants for repairing dGuo+• by ROH and by RO- via a SET mechanism are 7.17×109 and 9.35×105 dm3 mol-1 s-1, respectively. The repair activity of ROH toward dGuo+• is better than that of RO-. The overall rate constant of repairing dGuo+• by trans-resveratrol is 7.17×109 dm3 mol-1 s-1.Therefore trans-resveratrol is an effective antioxidant to repair the base radicals of dGuo and dGuo+•. The work presented in this paper was the first theoretical study on repairing DNA radicals with polyphenol. In particular, it provides information on the repairing pathways of two forms of trans-resveratrol under biological conditions, and this study can help us understand the repair activity of trans-resveratrol toward DNA radicals. ASSOCIATED CONTENT Supporting Information Distribution diagram of trans-resveratrol and the molar fractions of ROH and RO- in physiological conditions (pH=7.4). Optimized transition state structures of reactions a4 to a7 in the gas phase at the M06-2X/6-311G(d,p) level. Optimized structures of reactant complexes (RC) and intermediates (IM) of reactions b1 to b3 in the gas phase at the M06-2X/6-311G(d,p) level. Optimized transition state structures of reactions b4 to b7 in the gas phase at the M06-2X/6-311G(d,p) level. Reaction distance RAB (m), mutual diffusion coefficient DAB (m2 s-1) of the reactants A and B, and diffusion rate constants kD (dm3 mol-1 s-1) for repairing base radicals of dGuo by ROH and RO- via an HT mechanism. Reaction distance RAB (m), mutual diffusion coefficient DAB (m2 s-1) of the reactants A and B, and diffusion rate constants kD (dm3 mol-1 s-1) for repairing base radicals of dGuo and dGuo+• by ROH and RO- via a SET mechanism. The radii a (m) of reactants in water and benzene phases, respectively. Cartesian coordinates of



the optimized transition state structures of reactions a1 to a7 in the gas phase at the M06-2X/6-311G(d,p) level. Tunneling corrections (κ) and reaction path degeneracies (σ) for the reactions a1 to a7 in the gas phase. Rate constant kTST (dm3 mol-1 s-1) obtained from TST calculations for reactions between trans-resveratrol and dGuo-radicals at 298.15K. Cartesian coordinates of the intermediates of reactions b1 and b2 in the gas phase at the M06-2X/6-311G(d,p) level. Cartesian coordinates of the optimized transition state structures of reactions b4 to b7 in the gas phase at the M06-2X/6-311G(d,p) level. Tunneling corrections (κ) and reaction path degeneracies (σ) for the reactions b1 to b7 in the gas phase. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] ORCID [email protected]: 0000-0001-8952-0480 Notes The authors declare no competing financial interest. ACKNOWLEDGMENT The authors thank the Nation Science Foundation of China (No.11274238) for the financial support to this work and also thank the project funded by the priority academic program development of Jiangsu higher education institutions (PAPD) and the project of scientific and technologic infrastructure of Suzhou (SZS201708).


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TOC Graphic


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Figure 1. (a) Neutral form of trans-resveratrol (ROH), (b) anionic form of trans-resveratrol (RO-) and (c) 2'deoxyguanosine (dGuo). 80x51mm (300 x 300 DPI)

ACS Paragon Plus Environment


Figure 2. Optimized transition state structures of reactions a1 to a3 in the gas phase at the M06-2X/6311G(d,p) level. 80x107mm (300 x 300 DPI)


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Figure 3 80x55mm (300 x 300 DPI)



Figure 4 80x66mm (300 x 300 DPI)


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Figure S1. Distribution diagram of trans-resveratrol and the molar fractions of ROH and RO- in physiological conditions (pH=7.4). 80x66mm (300 x 300 DPI)



Figure S2. Optimized transition state structures of reactions a4 to a7 in the gas phase at the M06-2X/6311G(d,p) level. 160x93mm (300 x 300 DPI)


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Figure S3. Optimized structures of reactant complexes (RC) and intermediates (IM) of reactions b1 to b3 in the gas phase at the M06-2X/6-311G(d,p) level. 119x154mm (300 x 300 DPI)



Figure S4. Optimized transition state structures of reactions b4 to b7 in the gas phase at the M06-2X/6311G(d,p) level. 160x129mm (300 x 300 DPI)


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TOC image 62x41mm (300 x 300 DPI)


Repair Activity of trans-Resveratrol toward 2'-Deoxyguanosine Radicals

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