Theoretical Studies on DNA-Photocleavage Efficiency and Mechanism

Article pubs.acs.org/JPCA

Theoretical Studies on DNA-Photocleavage Efficiency and Mechanism of Functionalized Ru(II) Polypyridyl Complexes Ti-Fang Miao,*,†,‡ Jun Li,§ Shuang Li,† and Na-Li Wang† †

School of Chemistry and Materials Science, Huaibei Normal University, Huaibei 235000, People’s Republic of China State Key Laboratory of Theoretical and Computational Chemistry, Changchun 130023, People’s Republic of China § Department of Chemistry, Guangdong University of Education, Guangzhou 510303, People’s Republic of China ‡

S Supporting Information *

ABSTRACT: Theoretical studies on the DNA-photocleavage mechanism and efficiency of some Ru(II) polypyridyl complexes as novel reagents have been carried out using the density functional theory (DFT) method. Stable DNAdocking models of Ru(II) polypyridyl complexes were obtained using the docking and DFT methods. The excited-state reduction potentials, electron-transfer (ET) activation energies, and intramolecular reorganization energies were theoretically calculated, and the corresponding frontier molecular orbitals of complexes were also presented. Based on these properties of excited states, the essential component of two different DNA-photocleavage mechanisms, i.e., the photoinduced oxidation−reduction mechanism and the singlet oxygen photosensitization mechanism, has been revealed, and the DNA-photocleavage efficiencies were reasonably explained, and hereby a complex with excellent DNAphotocleavage ability was also designed. This work offers valuable theoretical insight into the property of excited-states and the DNA-photocleavage mechanism of Ru(II) polypyridyl complexes as novel reagents.

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INTRODUCTION Ru(II) polypyridyl complexes, owing to their excellent photophysical properties and DNA photocleavage ability, have received particular attention in bioinorganic chemistry.1−3 Recently, the DNA-photocleavage ability and mechanism of Ru(II) polypyridyl complexes were investigated experimentally and widely. The research results show that most Ru(II) polypyridyl complexes can cleave DNA in varying degrees under light irradiation and perform the mechanisms of a photoinduced oxidation−reduction and a singlet oxygen (1O2) photosensitization based on their different typies. That is, the oxidizing-type Ru(II) polypyridyl complexes, having high reduction potential under light irradiation, can effectively cleave DNA and thus mainly perform a photoinduced oxidation−reduction mechanism;4,5 the nonoxidizing-type Ru(II) polypyridyl complexes, having low reduction potential under light irradiation, mainly perform a singlet oxygen (1O2) photosensitization mechanism.6,7 Although the DNA-photocleavage abilities for most Ru(II) polypyridyl complexes have been preliminarily elucidated in experiment, so far, the factors affecting the DNA-photocleavage efficiency (ϕ) and the details of the interaction mechanism remain unclear for experimental chemists. Moreover, the theoretical insight into this field is still very limited, particularly, theoretical study of the singlet oxygen photosensitization mechanism is very infrequent. Therefore, theoretical studies on DNA photocleavage behaviors are of great significance for understanding the interaction mechanism, and directing the design of novel DNA-photocleavage reagents. The oxidizing-type Ru(II) complexes generally cleave DNA by their high reduction potentials, which can oxidize DNA, leading to the oxidation−reduction reaction between them. The © 2014 American Chemical Society

degree of electron-transfer from DNA to complex plays a key role in the DNA-photocleavage efficiency for these complexes. The nonoxidizing-type Ru(II) polypyridyl complexes cleave DNA mainly by singlet-state 1O2 as intermediate owing to their low reduction potentials, and thus the quantity of 1O2 produced by photoradiation is the key factor affecting the DNAphotocleavage ability of the complex. To perform the theoretical study on this field, the density functional theory (DFT) method was adopted, since the DFT calculation has a good accuracy and reasonable cost, and thus becomes a useful tool for the calculations of various molecular properties, such as electronic excitation, reaction mechanism, electron-transfer or polarizabilities in medium and so on.8−10 Meanwhile, to explore the DNA-photocleavage efficiency of Ru(II) polypyridyl complexes by 1O2 mechanism, we select the experimentally well-reported Ru(II) polypyridyl complexes 1− 3, i.e., [Ru(bpy)2dppz]2+, [Ru(phen)2ppd]2+, and [Ru(phen)(ppd)2]2+ (bpy = 2,2′-bipyridine, phen = 1,10-phenanthroline, dppz = dipyrido[3,2-a:2′,3′-c]phenazine, ppd = pteridino[6,7f ][1,10]phenanthroline);7 to explore the DNA-photocleavage efficiency of Ru(II) polypyridyl complexes by photoinduced oxidation−reduction mechanism, we select the experimentally well-reported Ru(II) polypyridyl complexes 4 and 5, i.e., [Ru(phen)2phehat]2+ and [Ru(tap)2phehat]2+ (tap = 1,4,5,8tetraazaphenanthrene, phehat = phenanthrolino[5,6-b]1,4,5,8,9,12-hexaazatriphenylene),4 to perform a theoretical study. In this work, the essential component of different Received: March 25, 2014 Revised: July 7, 2014 Published: July 9, 2014 5692

dx.doi.org/10.1021/jp502937b | J. Phys. Chem. A 2014, 118, 5692−5699

The Journal of Physical Chemistry A

Article

Figure 1. Structural diagrams of the complexes 1−6 and dGMP.

respectively, and that all computed spin contaminations S2 are zero using UB3LYP (see Table S-1, Supporting Information). This indicates that the spin contamination can not affect the computed results. Moreover, the obtained results were nearly equivalent by using these two methods. This shows that a closed-shell Ru(II) complex can be also optimized using UB3LYP, and the obtained results must be reliable. 2. Geometic Optimization of dGMP. In order to compute the electron-transfer (ET) activation energies between Ru(II) complexes and DNA, we replace DNA with dGMP (model) compound (see Figure 1), since DNA is a supramolecular system. The dGMP model process is given as follows: (1) the DNA crystal structure (downloaded from the Protein Data Bank) was sheared, and only a guanine, a pentose, and a PO4− were retained, and the edges of the cuts were saturated with the hydrogen atoms. Hence the rough geometry of dGMP was obtained. (2) Based on the obtained the rough geometry, dGMP was further optimized at the same level of theory as the complex, and the stable geometry of dGMP was obtained. 3. Geometic Optimization of Docking Model. The optimized structures of these complexes were docked with the optimized dGMP using the Dock6.0 program.13−15 The box size, grid space, energy cutoff distance, and maximum orientation were set as 20 Å, 0.3 Å, 9999 Å, and 200 000, respectively. The other parameters used in docking were the default, and thus the docking models (complex-dGMP) were obtained. The optimizations of the obtained docking models in ground state were further carried out at the above level of theory, and the optimized results are given in Figure 2. Meanwhile, the frequency calculation was also performed in order to verify the optimized docking model to be an energy minimum. In addition, to obtain the excited properties of the docking models, the docking models in the lowest triplet states (with triplet multiplicity) were also optimized using the same method, and we used the docking models in the lowest triplet states as the excited complex-dGMP, since our previous studies show that the DNA-photocleavage processes of Ru(II)

DNA-photocleavage mechanisms of these complexes will be revealed via the exact DFT calculations of the excited-state properties. In particular, to obtain high effective DNAphotocleavage reagents, a new Ru(II) complex 6 [Ru(tap)2taphat]2+ (see Figure 1) with stronger DNA-photocleavage ability was designed based on the calculations of reduction potentials of complexes 4 and 5. We hope that these theoretical studies can offer some useful insight into the property of excited-state of Ru(II) polypyridyl complexes and the corresponding action mechanism with DNA.

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COMPUTATIONAL METHODS 1. Geometric Optimizations of Complexes in GroundState and Excited-State. The structural diagrams of the studied complexes 1−6 are shown in Figure 1. It can be seen that each of the complexes 1−6 forms from Ru(II) ion, one intercalative ligand (dppz, ppd, phehat, or taphat), and two ancillary ligands (bpy, phen, or tap). Full geometry optimization of the complexes in the ground state was carried out using the unrestricted B3LYP method with the LanL2DZ basis set11,12 for Ru atom and with the 6-31G(d) basis set for the other atoms. For the obtained structures, the frequency calculations were also performed using the same method in order to verify that the optimized structure was an energy minimum. For geometic optimization of the complexes in excited state, we use the lowest triplet-state geometries (T1, with triplet multiplicity) which were optimized in vacuo using the above method at the same level of theory. Meanwhile, frequency calculations were also performed using the same method to verify that the optimized structure was an energy minimum. The restricted DFT method would be most suitable for singlet ground states. The unrestricted DFT method, capable of treating unpaired electrons, would be most suitable for open shell systems. Based on many calculations of Ru(II) polypyridyl complexes, we can see that closed-shell Ru(II) complexes have been optimized using UB3LYP and B3LYP methods, 5693



Article o E[Ru(bpy) L](n + 1) + /[Ru(bpy) L]n + 2

=−

2

o o ΔG[Ru(bpy) − ΔGSCE L](n + 1) + /[Ru(bpy) L]n + 2

2

(1)

nF

where o o ΔG[Ru(bpy) = −ΔGaq L](n + 1) + /[Ru(bpy) L]n +

(2)

o o ΔGaq = ΔGgas + ΔGo(2) − ΔGo(1)

(3)

o o o ΔGgas = ΔHgas − T ΔSgas

(4)

o o ΔHgas = ΔεSCF + Δεtrans + Δεrot + Δεvib + ΔεZPE

(5)

2

Figure 2. Optimized ground-state docking models of complexes 1−6 with dGMP.

2

ΔG o(2) = G o[Ru(bpy)2 L](n + 1) + (aq) − G o[Ru(bpy)2 L](n + 1) + (gas)

(6)

polypyridyl complexes happen at the geometries of complexes in the lowest triplet states.16 4. Calculation of Oxidation−Reduction Potential. Geometries of complexes 1−6 were completely optimized using the unrestricted B3LYP method and the abovementioned basis set. Based on their optimized geometries in the ground-states (S0), the Gibbs free energies were obtained via single-point computations in vacuo; meanwhile the Gibbs free energies in aqueous solution were also obtained from their single point calculations in aqueous solution with the conductor polarized continuum model (CPCM)17,18 at the same level of theory. Based on their optimized geometries in the lowest triplet-states (T1), the Gibbs free energies in vacuo and in aqueous solution were obtained via single-point computations at the same level of theory. Scheme 1 was adopted to calculate the standard redox potentials of these Ru(II) complexes in the ground state (S0)

o

n+

o

o

n+

ΔG (1) = G [Ru(bpy)2 L] (aq) − G [Ru(bpy)2 L] (gas) (7)

H+(aq) + e−(gas) →

1 H 2(gas) 2

1 Hg Cl 2(aq) + e(g) → Hg + Cl−(aq) 2 2

(8) (9)

All of the related free energies were calculated under standard conditions, i.e., at 298.15 K and 1 bar, with the concentration of complex in aqueous solution at 1 mol L−1 and in the gas at 1 mol L−1. 5. Calculations of ET Activation Energy. According to the theory of Marcus semiclassical model,22,23 which is the main approach dealing with the nonadiabatic ET process, the rate constant of ET reaction is given as follows:

Scheme 1. Thermodynamic Cycle Used to Calculate the Redox Potentials in Solution

ket =

1/2 2π 2 ⎛ 1 ⎞ ⎟ HDA ⎜ exp[−Ec /(RT )] ⎝ 4πλRT ⎠ ℏ

(1)

where h is the Planck’s constant, T is the temperature, HDA is the ET matrix element, λ is the reorganization energy, and Ec is the ET activation energy. The activation energy Ec can be expressed as follows:24 Ec = (ΔG° + λ)2 /4λ

(2)

where ΔG° is the standard Gibbs free energy change of the ET reaction. 5.1. Calculation of the Reorganization Energy λ. Under light irradiation, electrons transfer from DNA to Ru(II) polypyridyl complexes,25 suggesting that such an ET process is actually a redox reaction between the complex and DNA. The reaction processes of complexes are given as follows:

and the lowest triplet-states (T1). The principle of this method is briefly presented as follows: In order to compare with experimental data, the standard redox potentials of the complexes in the ground state relative to the standard calomel electrode (SCE) can be calculated using eq 1 on the basis of the thermodynamic cycle as shown in Scheme 1. The Gibbs free energy change of the standard hydrogen electrode (SHE) (ΔG◦SCE =−4.43 eV) is from the experimental value,19 which is equal to the Gibbs free energy change of eq 8. The Gibbs free energy change of SCE (ΔG◦SCE = −4.1888 eV) was obtained via adding 0.2412 eV (the standard potential of SCE relative to SHE is −0.2412 V) to that of SHE (−4.43 eV),20,21 which is equal to the Gibbs free energy change of eq 9.

[Ru(phen)2 L]2 + + DNA → [Ru(phen)2 L]1 + + DNA+ (3)

Reaction 3 depends on how difficult it is to transfer electrons between Ru(II) complex and DNA, which is dominated by the ET activation energies. However, the calculations of ET activation energies between Ru(II) complexes and DNA are very difficult, since DNA is a supra-molecular system. Here, we replace DNA with dGMP (model) compound (see Figure 1). The reaction of dGMP with Ru(II) complex is as follows: [Ru(phen)2 L]2 + + dGMP → [Ru(phen)2 L]1 + + dGMP+ (4) 5694



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Table 1. Calculated Standard Redox Potentials (Eox and Ered) (V) in the Ground State and (E*ox and E*red) (V) in the Excited State for Complexes 1−6 and the Corresponding Experimental Values

According to reaction 4, the reorganization energy (λ), associating with relaxing the geometry of the system after ET, is the average values of λ1 (the reorganization energy of dGMP) and λ2 (the reorganization energy of Ru complex), i.e., λ=

λ1 + λ 2 2

(5)

Since electrons transfer from DNA to complex under light irradiation, in order to obtain the accurate reorganization energy, we replace the [Ru(phen)2L]2+ and dGMP in reaction 4 with the complex and dGMP in the optimized docking model in the ground state, respectively. Similarly, we replace the [Ru(phen)2L]1+ and dGMP+ in reaction 4 with the complex and dGMP in the optimized docking model in the lowest triplet state, respectively. We first obtain the total energy of E(dGMP) at its geometry in the optimized docking model in the ground state, and the total energy of E(dGMP+) at its geometry in the optimized docking models in the lowest triplet state. On the other hand, we also calculate the energy E′(dGMP) at the geometry of dGMP+ and the energy E′(dGMP+) at the geometry of dGMP. Thus, we obtain the reorganization energy λ1 by

(6)

Similarly, we obtain the reorganization energy λ2 by λ 2 = E′[Ru(phen)2 L]2 + + E′[Ru(phen)2 L]1 + − E[Ru(phen)2 L]2 + − E[Ru(phen)2 L]1 +

(7)

The total reorganization energy was obtained via eqs 5, 6, and 7. 5.2. Calculation of the Standard Gibbs Free Energy Change ΔG◦. Ru(II) polypyridyl complex binding to DNA can change from the ground state to the excited state under light irradiation; such a process can be expressed as follows: dGMP‐complex → ′dGMP‐complex

(8)

Where dGMP-complex and ′dGMP-complex express the docking models (dGMP-complex) in the ground state and in the excited state, respectively. The standard Gibbs free energy change (ΔG◦) in reaction 8 was obtained by ΔG° = G′(dGMP‐complex) − G(dGMP‐complex)

Eox

Ered

E*ox

E*red

1.417 1.24 1.587 1.652 1.353 1.35 2.080 2.380

−0.745 −1.02, −1.44, −1.67 −0.546 −0.519 −0.642 −0.84 −0.486 −0.336

−0.729

1.041 0.97 1.153 1.187 1.416 1.10 1.881 1.921

−0.112 −0.053 −0.705 −0.55 −0.287 −0.511

with water as the solvent. The CPCM model does not take into account H-bonds, whereas the studied complexes have strong polar property and thus they easily interact with H2O molecules, leading to the H-bonds between the complex and H2O molecules. So the imprecise solvation energy without considering the H-bonds may be the reason leading to the error of the computed energy. The calculated excited-state reduction potentials (E*red) of complexes 1 and 4 are 1.041 and 1.416 V, respectively, corresponding experimental values 0.97 V27 and 1.10 V,28 respectively. The computed results show that the dipole moments of ground-state complexes 1 and 4 in vacuo are 7.269 and 15.859 D, respectively, and those in aqueous solution are 11.840 and 21.794 D, respectively. This indicates that the greater the dipole moment is, the greater the error of the computed excited-state reduction potentials of these complexes is. This also implies that the polar property of complex affects the computed result of excited-state reduction potential. In addition, the excited-state redox potentials of complexes 1 and 4, with experimental results, were recomputed with the above method. Meanwhile, the UB3LYP-D3 method with the LanL2DZ basis set for Ru atom and with the 6-31G(d) basis set for the other atoms adding the dispersion terms was performed for testing the effect of dispersion. The obtained data are listed in Table S2. The computed E*red values of complex 1 and 4 are, respectively, 1.028 and 1.443 V, which are close to the computational results (1.041 and 1.416 V) using UB3LYP method. Such a result shows that the computed excited-state reduction potentials (E*red) using UB3LYP and UB3LYP-D3 methods are nearly equivalent. This also shows that the bias introduced by the absence of dispersion treatment in our calculations is acceptable. Table 1 shows that the computed excited-state reduction potentials (E*red) of complexes 1−6 based on the optimized geometries in the lowest triplet state are 1.041 V, 1.153 V, 1.187 V, 1.416 V, 1.881 and 1.921 V, respectively, showing that complexes 4−6 can oxidize the guanine of DNA based on mainly performing a photoinduced oxidation−reduction mechanism, due to their E*red obviously higher than the oxidation potential of guanine (G) EG+/G (1.05 V versus SCE).29 Moreover, the E*red order of complexes 4−6 is E*red(6) > E*red(5) > E*red(4), showing that the trend in DNAphotocleavage efficiencies (ϕ) of complexes 4−6 can be expected as follows: ϕ(6) > ϕ(5) > ϕ(4), since a complex with a high E*red always has a strong oxidation ability.30 This is in accordance with the experimental result,4 being ϕ(5) > ϕ(4). So we can predict that the oxidation abilities of designed complex 6 with the highest E*red are stronger than those of complexes 4 and 5.

λ1 = E′(dGMP) + E′(dGMP+) − E(dGMP) − E(dGMP+)

comp. 1 expt.27 2 3 4 expt.28 5 6

(9)

where G(dGMP‑complex) and G′(dGMP‑complex) are the energies of the optimized docking model in the ground state and in the lowest triplet state, respectively. Meanwhile, the correction to Gibbs free energy was added to G and G′. The above calculations were preformed with the Gaussian09 program package.26

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RESULTS AND DISCUSSION 1. Computed Redox Potentials of Complexes. The calculated redox potentials of complexes 1−6 are also listed in Table 1, and all data were calculated at standard conditions (see Table S-2) on the basis of the optimized geometries of complexes 1−6 in vacuo and the calculations of single point energies. Table 1 shows that all calculated redox potentials, especially excited-state redox potentials of complexes 1 and 4 in vacuo, deviate from the experimental results in various degrees. Such errors may be attributed to the imprecise solvation energy, which was calculated using an approximate model (CPCM) 5695



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the strongest, and that between 2 and DNA should be the weakest, i.e., the DNA-photocleavage efficiencies (ϕ) of complexes 1−3 should be ϕ(1) > ϕ(3) > ϕ(2). This order seems to be inconsistent with experimental result,7 being ϕ(3) > ϕ(2) > ϕ(1). However, such a disagreement may be explained from intramolecular reorganization energy (λ2). As is well-known, complexes 1−3 can change from the ground state to the excited state and undergo an intramolecular electron transfer under light irradiation, moreover, the excitedstate complexes can rapidly react with oxygen molecules around to produce the quite active singlet oxygen.31,32 Therefore, the intramolecular electron transfer in complexes 1−3 may be the key factor affecting the quantity of singlet oxygen. The intramolecular reorganization energy is relaxation energy from the ground state to the excited state, and its value means a difficult degree of ET when electrons are excited. Table 2 also shows that the computed intramolecular reorganization energy (λ2) of complexes 1−3 are 0.0065, 0.0043, and 0.0039, respectively, suggesting that intramolecular ET in complex 3 occurs much more easily, that in complex 2 follows, and that in complex 1 occurs with difficulty. Therefore, complex 3 can easily react with oxygen molecules around to produce the most active singlet oxygen, whereas complex 1 should be in contrast, in accordance with the 1O2 generation quantum yield7 of complexes 1−3 to be 0.09, 0.37, and 0.50. Synthetically considering these two factors, the DNA-photocleavage abilities of complexes 1−3 should be ϕ(3) > ϕ(2) > ϕ(1). 3. Molecular Orbital Analysis. The highest occupied molecular orbitals (HOMOs) and the lowest unoccupied molecular orbitals (LUMOs) of complexes 1−6 and their docking models in ground states are given in Figure 3, and the relevant HOMO−1 and LUMO+1 of complexes 1−6 are also given in Figure S-2. It can be seen that electrons of HOMO of docking models in ground states are mainly distributed on dGMP, whereas those of LUMO of docking models are mainly distributed on the ancillary ligands of complexes. This indicates that electrons transfer from dGMP to the ancillary ligands of complexes when electrons are excited. This also implies that the electron-transfer process, i.e., from DNA (dGMP) to complexes,33,34 is a process of oxidation−reduction reaction, in which the DNA-base-pairs will be oxidized. However, the DNA photocleavage may depend upon high excited-state reduction potentials in such oxidation−reduction reactions. From Figure 3 and Figure S-2, we can also see that electrons of HOMO and HOMO−1 for complexes 4−6 in ground states are concentrated on the ends of the intercalative ligands, whereas those of LUMO and LUMO+1 of complexes 4−6 are mainly distributed on the ancillary ligands of complexes. This is advantageous to forming π−π stacking interactions between DNA and the intercalative ligands; moreover, when electrons are excited, it is easy to lead to electron-transfer from DNA to intercalative ligand of complex and further transfer from intercalative ligand to ancillary ligand. Such an electron-transfer manner must be greatly advantageous to the oxidation− reduction reaction between complex and DNA. Therefore, complexes 4−6, with high excited-state reduction potentials, can directly clave DNA by the 3ILCT (intraligand chargetransfer), that is to say, their DNA-photocleavage mainly performs a photoinduced oxidation−reduction mechanism. For complexes 1−3, electrons of HOMO and HOMO−1 in ground states are mainly distributed on metal atoms, the intercalative ligands, and the ancillary ligands, whereas those of LUMO and LUMO+1 in ground states are mainly distributed on the

On the other hand, the computed excited-state reduction potentials (E*red) of complexes 1−3 are 1.041, 1.153, and 1.187 V, the E*red of complexes 2 and 3 are only appreciably higher than the oxidation potential of guanine (G) EG+/G (1.05 V versus SCE).29 This is a result of the following: (1) there is not a substantial different for the oxidation−reduction potentials among these excited-state complexes and guanine (G) of DNA, so that such an appreciable different can be attributed as theoretical error, and (2) the computed ground-state dipole moments of complexes 1−3 are 7.269, 13.968, and 13.807 D, respectively, showing that the computed excited-state reduction potentials of complexes 2 and 3 should be affected rather by the H2O molecules relative to complex 1. According to the computed E*red of the complex (see complexes 1 and 4), which is always higher than the experimental result, especially for the effect of polar property, it is worth to believing that the E*red of complexes 2 and 3 should not be substantially higher than the oxidation potential of guanine (G) EG+/G (1.05 V versus SCE). Therefore, complexes 1−3 can not directly oxidize the guanine of DNA based on a photoinduced oxidation−reduction mechanism, but they can perform a singlet oxygen (1O2) photosensitization mechanism, in accordance with experimental result.7 2. ET Activation Energies. The computed standard Gibbs free energy change (ΔG◦), reorganization energy (λ) and activation energy (Ec) of ET (electron-transfer) reaction are given in Table 2. Table 2 shows that ET activation energies of Table 2. Calculated λ1 (dGMP), λ2 (Complex), λtot, ΔG◦ and Ec for Complexes 1−6a

a

xomp.

λ1

λ2

λtot

ΔG°

Ec

1 2 3 4 5 6

0.0013 0.0013 0.0015 0.0119 0.0135 0.0392

0.0065 0.0043 0.0039 0.0034 0.0063 0.0042

0.0039 0.0028 0.0027 0.0076 0.0099 0.0217

0.0699 0.0749 0.0729 0.0765 0.0693 0.0470

0.3485 0.5358 0.5328 0.2316 0.1581 0.0543

All energy values in a.u.

complexes 4−6 are much lower than those of complexes 1−3. Such a result suggests that complexes 4−6 possess high excitedstate reduction potentials based on their low ET activation energies, whereas complexes 1−3 possess low excited-state reduction potentials based on their high ET activation energies. Meanwhile, based on the order of the excited-state reduction potentials for complexes 4−6, i.e., 1.416, 1.881, and 1.921 V, respectively, it is easy to expect that the DNA-photocleavage efficiencies (ϕ) are ϕ(6) > ϕ(5) > ϕ(4), in accordance with experimental result4 being ϕ(5) > ϕ(4). This shows that the oxidizing ability of complex 6 is the strongest, that of complex 5 follows, and that of complex 4 is the weakest, i.e., the oxidation−reduction reaction between complex 6 and DNA should be the strongest and that between complex 4 and DNA should be the weakest. Furthermore, it means that ET between complex 6 and DNA occurs much more easily, whereas ET between complex 4 and DNA occurs with difficulty, i.e., the ET activation energy (Ec) between complex 6 and DNA should be low, whereas that between complex 4 and DNA should be high, in accordance with our computed results (see Table 2). For complexes 1−3, their ET activation energies are 0.3472, 0.5358, and 0.5328, respectively. Such a result shows that the oxidation−reduction reaction between 1 and DNA should be 5696



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and 3 when electrons are excited, such a 3MLCT manner is advantageous to electrons spread over the intercalative ligands and the ancillary ligands, leading to more radicals formed on the intercalative ligands and the ancillary ligands. These radicals can react to the O2 around, and thus many 1O2 are produced. In contrast, since electrons transfer mainly from the intercalative ligand and metal atom to the ancillary ligand for complex 1 when electrons are excited, such an electron-transfer manner favors radicals only formed on the ancillary ligands, leading to few 1O2 produced relative to complexes 2 and 3. Therefore, the DNA-photocleavage abilities of complexes 2 and 3 should be stronger than that of complex 1, consistent with experimental result.7 Two single occupancy orbitals (HOMO and HOMO−1) of complexes 1−6 and their docking models in the triplet states were also computed, and the computed results are given in Figure S-1. It can be seen that electrons of HOMO−1 of docking models in the triplet states are mainly distributed on dGMP, whereas those of HOMO of docking models are mainly distributed on the ancillary and intercalative ligands of complexes. This indicates that electrons transfer from dGMP to the complex when electrons are excited. From the LUMO of complexes 1−6 in ground state, we can see that electron excitation leads to a great deal of electrons distributed on the ancillary ligands of complexes (see Figure 3). Such an excitation manner is advantageous to the interactions between DNA and the ancillary ligands via hydrogen bonds4 and producing more 1 O2, which can also increase the DNA-photocleavage abilities of the complexes. 4. DNA-Photocleavage Mechanism. Ru (II) polypyridyl complexes cleaving DNA mainly perform the photoinduced oxidation−reduction and singlet oxygen photosensitization mechanisms. Complexes 4−6 cleave DNA mainly by the photoinduced oxidation−reduction and have three characteristics: (1) high excited-state reduction potentials, (2) low ET activation energies between DNA and them, and (3) longer ET distances during electron excitation. Both the order of computed excited-state reduction potentials (E* red (6) >E*red(5) > E*red(4)) and the order of computed ET activation energies (Ec(4) >Ec(5) > Ec(6)) are all in accordance with experimental results.4 This shows that the oxidation−reduction reaction plays an important in DNA-photocleavage for complexes 4−6. Complexes 1−3 mainly perform the singlet oxygen photosensitization mechanism and also have three characteristics: (1) low excited-state reduction potentials, (2) high ET activation energies between DNA and them, and (3) shorter ET distances during electron excitation. This shows that complexes 1−3 cleave DNA not by the oxidation−reduction reaction, but by the singlet oxygen 1O2 produced. The quantity of produced 1O2 relates to the difficulty degree of ET, i.e., electron distribution in the excited-state complex. When electrons transfer from metal atom to the intercalative ligand and the ancillary ligand, such an ET manner is easy to occur and favors more 1O2 produced, and thus the complex will have strong DNAphotocleavage ability.

Figure 3. Molecular orbitals of complexes 1−6 and their DNA docking models 1−6′ ((H atoms are not shown) in ground states.

ancillary ligands and intercalative ligands of complexes. When electrons are excited, the electron-transfer happens from metal atoms to the intercalative ligands and the ancillary ligands for complexes 2 and 3, and from the intercalative ligand and metal atom to the ancillary ligand for complex 1. So the oxidation of the guanine is performed by 3MLCT (metal-to-ligand charge transfer) for complexes 2 and 3, whereas by both the 3ILCT and 3MLCT for complex 1. Since the 3ILCT of complex 1 is naturally weaker than those of complexes 4−6, leading to the excited-state reduction potential of complex 1 lower than the oxidation potential of guanine (G) EG+/G (1.05 V versus SCE). It may be the reason that complex 1 can not directly cleave DNA by its E*red. However, excited complex 1 can also produce singlet oxygen 1O2 via the interaction between the ancillary ligands and surrounding O2, and thus its DNA-photocleavage, just as excited complexes 2 and 3, performs a singlet oxygen photosensitization mechanism. In addition, we can see that the electron-transfer distances of complexes 4−6 are far away when electrons are excited. Such an intramolecular electron-transfer manner of complexes 4−6 may lead to high excited-state reduction potentials, hence complexes 4−6 cleave DNA mainly by the oxidation−reduction reaction. On the contrary, the electron-transfer distances of complexes 1−3 are not far away when electrons are excited. Such an intramolecular electrontransfer manner may lead to low excited-state reduction potentials. Since electrons transfer from metal atom to the intercalative ligands and the ancillary ligands for complexes 2

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CONCLUSIONS Theoretical studies on DNA-photocleavage mechanism and efficiency of Ru (II) polypyridyl complexes 1−6 have been carried out using the docking and DFT methods. The essential component of two different DNA-photocleavage mechanisms, i.e., the photoinduced oxidation−reduction mechanism and the 5697



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singlet oxygen photosensitization mechanism, has been revealed via computed excited-state reduction potentials and ET activation energies. Moreover, their DNA-photocleavage efficiencies were also reasonably explained. Theoretical results show the following: (1) The stable DNA-docking models of complexes were obtained using the docking and DFT methods. (2) Complexes 4−6 perform a DNA-photocleavage mechanism since they have quite high excited-state reduction potential and lower ET activation energy, and hereby the DNA-photocleavage efficiencies of ϕ(6) > ϕ(5) > ϕ(4) were reasonably explained, in which complex 6 is the designed complex with excellent DNA-photocleavage ability. (3) Complexes 1−3 perform a singlet oxygen photosensitization mechanism since they have lower excited-state reduction potential and higher ET activation energy; moreover, their DNA-photocleavage efficiencies of ϕ(3) > ϕ(2) > ϕ(1) were also reasonably explained by the intramolecular reorganization energies and the frontier molecular orbitals of complexes.

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ASSOCIATED CONTENT

S Supporting Information *

Spin contamination (Table S-1), redox-potential data (Table S2), molecular orbitals (Figures S-1 and S-2), and spin densities (Figure S-3). This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] (T.-F. Miao). Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are pleased to acknowledge the financial support of the National Natural Science Foundation of China (20903025), and the financial support of the Research Foundation of the State Key Laboratory of Theoretical and Computational Chemistry (No. k2013-04), and the Science and Technology Talent Development Foundation of Huaibei (No. 20130305).

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REFERENCES

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Theoretical Studies on DNA-Photocleavage Efficiency and Mechanism

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