Theoretical Studies on the Photophysics and Photochemistry of 5

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Theoretical Studies on the Photophysics and Photochemistry of 5-Formylcytosine and 5-Carboxylcytosine-----the Oxidative Products of Epigenetic Modification of Cytosine in DNA Jinlu Xing, Yuejie Ai, Yang Liu, Jia Du, Weiqiang Chen, Zhanhui Lu, and Xiangke Wang J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.7b10218 • Publication Date (Web): 22 Feb 2018 Downloaded from http://pubs.acs.org on February 23, 2018

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The Journal of Physical Chemistry

1

Theoretical Studies on the Photophysics and Photochemistry of

2

5-Formylcytosine

3

Products of Epigenetic Modification of Cytosine in DNA

4

Jinlu Xing, a,b Yuejie Ai, a,* Yang Liu, a Jia Du, b Weiqiang Chen, a,b Zhanhui Lu,b,* and Xiangke

5

Wang a,c,d,*

6

a

7

Beijing 102206, P.R. China.

8

b

9

102206, P.R. China.

and

5-Carboxylcytosine-----the

Oxidative

College of Environmental Science and Engineering, North China Electric Power University,

School of Mathematics and Physical Science, North China Electric Power University, Beijing

10

c

11

Arabia.

12

d

13

School for Radiological and Interdisciplinary Sciences, Soochow University, Suzhou 215123, P.R.

14

China.

15

*: Corresponding author. Email: [email protected] (Yuejie Ai), [email protected]

16

(Zhanhui Lu) and [email protected] (Xiangke Wang).

NAAM Research Group, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi

Collaborative Innovation Centre of Radiation Medicine of Jiangsu Higher Education Institutions,

ACS Paragon Plus Environment

The Journal of Physical Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Abstract

18

Cytosine methylation and demethylation play crucial roles in understanding the genomic

19

DNA expression regulation. The epigenetic modification of cytosine and its continuous oxidative

20

products—the

21

5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), 5-carboxylcytosine (5caC). However,

22

compared to the abundant studies on the classical DNA bases, the photophysical and

23

photochemical properties of those new bases have not yet aroused people's excessive attention. In

24

this contribution, a systematic study on the non-radiative decay and photochemical pathways via

25

excited states or conical intersections upon photo-excitation have been explored through

26

high-level computational approaches such as the complete active space self-consistent field

27

(CASSCF) method, complete active space with second-order perturbation theory (CASPT2) and

28

density functional theory (DFT). Pathways like the ring-distortion deactivation, hydrogen

29

dissociation, hydrogen transfer and also Norrish type I and II photochemical reactions have been

30

investigated and it was proposed that intersystem crossing (ISC) from S1 state to T1 state is the

31

most effective route for 5fC. While for 5caC, ring-pucking and intra-molecular isomerism are

32

effective deactivation ways at both neutral and protonated forms. In the meantime, the influences

33

of two important environmental factors: the solution and acidic environment (i.e. the protonated

34

state) were also considered in this study. From theoretical perspective, the initial properties of the

35

photo-stability and photochemical reactivity for 5fC and 5caC have become a crucial aspect to

36

facilitate a further comprehension of their potential role in gene regulation and transcription.

37

1. Introduction

“new

four

bases

of

DNA”

including

5-methylcytosine

(5mC),

38

Deoxyribonucleic acid (DNA) cytosine methylation is a predominant epigenetic

39

modification that plays an essential role in gene regulation, genome stability, transcription

40

and the development of a variety of human cancer and diseases1, 2. Starting from the

41

5-methylcytosine (5mC) (a methyl group substituted to the 5-position of the cytosine),

42

under the effect of Ten-eleven translocation (TET) family for enzymes, the continuous

43

oxidation of 5mC produces its further oxidized states: 5-hydroxymethyl cytosine (5hmC),

44

5-formylcytosine (5fC), and 5-carboxylcytosine (5caC)3-5. In recent years, 5mC and its


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45

sequential oxidation products are now considered as the “new” four bases of DNA and

46

have become a new research hotspot except for the canonical Watson and Crick bases,

47

since they comprise a feasible paradigm for the active DNA demethylation via sequential

48

oxidation, base excision, and subsequent repair6, 7.

49

The studies of 5fC and 5caC have attracted people's attention since they can be

50

identified and excised by thymine-DNA glycosylase (TDG) protein to integration of

51

non-modified cytosine followed by base excision repair (BER) pathway, which was

52

considered as a key approach for active demethylation process of DNA4, 8-12. However, the

53

content of 5fC presents at a level of ~0.002% of all cytosines in mouse ES cells , approxi-

54

mately 100-fold lower than that of 5hmC13, 14. The 5caC has been detected at a level of

55

~0.0003%, which is ten times lower than 5fC level10, 12, 15. It becomes a challenge for

56

quantitative and high-resolution analysis due to such low abundance in mammalian

57

genomic DNA16. Therefore, the experimental research of 5fC and 5caC is still in its infancy

58

due to the lack of fine structural data, effective single-base resolution sequencing methods

59

and analysis technology etc. What's worse, there are numerous intermediates and reaction

60

steps that are difficult to capture in DNA demethylation activity. Quantum chemical

61

calculations are viable complement to the above experiments in addressing various

62

problems and have been successfully applied in the studies related to the origin of life such

63

as DNA and RNA14, 17-19.

8

64

However, even given the essential significance of the new four bases to various

65

aspects in epigenetic modifications, little attention was paid to the theoretical study on

66

5mC and its derivatives. Recently, Luo's team had investigated the catalytic mechanisms

67

and substrate preference for oxidations of 5mC, 5fC and 5hmC that catalyzed by TET2

68

proteins using MD and hybrid QM/MM approaches. Besides, Dai et al.20. applied the

69

density functional theory (DFT) together with the IR spectroscopy to investigate the pKa of

70

N9 (see Scheme 1) protonated 5fC/5caC and assigned the more acidic pKa value of 5caC.

71

Jin and co-workers21 studied the activation free energies for the HSO3- induced

72

deamination mechanism for 5caC and 5fC under typical bisulfite conditions by

73

MP2//B3LYP method. Moreover, others presented DFT and classical MD simulations on

74

the detailed configuration of (caC)2-calcium salt deposited on the highly oriented pyrolytic



75

graphite surface22. In summary, most of the previous theoretical studies were focusing on

76

the relevant chemical reactions and interaction with either TET protein in the catalytic

77

cycle or metal ion, while the theoretical study on the initial properties such as

78

photophysical and photochemical properties of the new four bases have received

79

surprisingly little attention. As the basic carrier for genetic information of DNA, the

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nucleobases displayed well-documented photo-stability under persistent irradiation with

81

ultraviolet light which could potentially induce deleterious structural damage or

82

photochemical reactions23. Such photo-stability can be mainly attributed to the availability

83

of non-radiative decay from the photo-excited state to the ground S0 state. Therefore, the

84

photo-stability is the decisive selection criterion for bases since the origin of life. For

85

heteroatom contained aromatic molecules24 and classic bases25, the photo-stability had been

86

investigated by plenty of experimental and theoretical studies. However, the structural and

87

energetic data on the photophysical and photochemical processes of the new four bases still

88

remained largely elusive so far. Very recently, Improta’s group studied the optical spectra26

89

and mechanism of the excited state decay of 5mC analogue27 in different solvents (water,

90

tetrahydrofuran, and acetonitrile) by combining spectroscopy experiments and QM

91

calculations. Four lowest energy excited states have been assigned and an “ethane-like”

92

conical intersection was involved in the main ultrafast non-radiative decay route, showing

93

a barrierless path for cytosine and a longer excited state lifetime for 5mC. Nevertheless,

94

few researches have sought to explore the photophysical and photochemical characteristics

95

of 5fC and 5caC, which prompted us to give a comprehensive theoretical study on this.

96

The current work aimed to study the photophysical and photochemical properties of

97

the 5fC and 5caC with quantum chemical calculations. Firstly, the geometrical and

98

energetic information for the ground state, excited state and conical intersection have been

99

studied. Based on these basic results, radiationless deactivation pathways and possible

100

photo-chemical reactions of 5fC and 5caC, including Norrish type I and Norrish type II

101

reactions have been investigated in detail. In addition, the influences of environmental

102

factors, including solvent effect and protonated state will be considered. The structural and

103

electronic calculations may provide an effort to the underlying mechanisms for the

104

photo-stability and photo-reactivity of 5fC and 5caC which are likely to give better


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105

understanding of the photochemistry of the new four bases and their involvement of active

106

DNA demethylation pathway in epigenetic modification.

107

2. Computational Details

108

In present work, the complete active space self-consistent field (CASSCF) method28, 29

109

coupled with 6-31G(d) basis set was used to locate the stationary points of the ground state

110

(S0), the excited state (S1) and also the conical intersections (CIs). The geometries were

111

firstly optimized at CAS(8,7) level which is eight electrons in seven orbitals. The active

112

orbitals for CASSCF calculations of 5fC and 5caC have been presented in the supporting

113

information, see Figure S1. Then CASPT2//CAS(14,10) single-point energies were

114

obtained based on the CAS(8,7) optimized structures with the MOLCAS 8.0 package30.

115

Such a CASPT2//CASSCF approach gives a better balance of computational cost and

116

accuracy and has been successfully applied in many studies19, 31-34. In addition, the rigid

117

scans of potential-energy profiles of ground and excited states for possible reaction

118

mechanisms were also studied using the hybrid exchange-correlation functional

119

CAM-B3LYP35 of density functional theory (DFT)36-38 and time-dependent DFT

120

(TDDFT)39-41.

121

The solvent effects on the reaction mechanism were mimicked with single-point

122

calculations by the polarizable continuum solvent model (PCM)42,

43

123

parametrization supported by the Gaussian 09 program44. All the calculations (except for

124

the CASPT2 computations) were carried out with Gaussian 09 software package44.

125

3. Results and Discussions

126

3.1. Protonation States and Stationary Structures for 5fC and 5caC

in the standard

127

Recently, Dai et al. have indicated that the 5fC and 5caC can be protonated at N9

128

position (see Scheme 1) at low pH value and the measurement pKa is 2.4 and 2.1 for 5fC

129

and 5caC, respectively20. We then applied the solvation model based on density (SMD)45

130

together with the self-consistent reaction field method46-48 to compute the corresponding

131

pKa value for 5fC and 5caC, as summarized in Table 1. The computed pKa value of the 5fC



Page 6 of 26

132

and 5caC were 1.46 and 1.72, respectively, which were a little lower than the experimental

133

ones, and the theoretical and experimental results both suggested that the neutral and

134

protonated forms are most likely in equilibrium at low pH for 5fC and 5caC. Since our

135

previous work proposed that, compared with the neutral state49, the protonated state may

136

have influence on the reaction mechanism. Consequently, both neutral and protonated

137

forms were considered in the following calculations.

138

Table

139

B3LYP/6-31G++(2d,2p)//B3LYP/6-311G(d,p) level.

1.

Calculated

pKa

value

by

the

SMD

Solvation

Structure

5fC

5caC

pKa Value

1.46

1.72

6

N

NH2

O 14

5

13

9 10

C

4 2

H

16 H

N9

H+

C

3

N

11 O

11 O

1

141

CH 3

13

4 2

N

NH2

O 16 OH 14

CH 3

H+

17 H

N

5

9 10

C

1

O 16 13

4 2

OH 14

CH

N

11 O

3

H12

H12

140

1

H

6

6

C

2

the

5fC-P

NH2 5

13

4

at

H 12

5fC-N

9 10

5

N

H 12

N

O 14

10

CH

1

11 O

6

NH2

Model

5caC-N

5caC-P

Scheme 1. Atomic label of neutral and protonated forms of 5fC and 5caC.

142

The optimized structures of the ground states (S0) and the first excited states (S1) of

143

neutral (5fC-N, 5caC-N) and protonated (5fC-P, 5caC-P) 5fC and 5caC are shown in

144

Figure 1. From Figure 1, we can see that compared with the geometry of S0, there were

145

some alternations of bond length and structural changes in the S1 state. In detail, for

146

example, the length of C13-O14 bond of 5fC-N amounts to 1.193 and 1.359 Å for the S0


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147

and S1 states, respectively. We depicted the molecular orbitals for the excitations in Figure

148

S2. It indicated that the S1 state of 5fC-N was involved in the n→π* excitation located on

149

the C13-O14. While the S1 state of 5caC-N was a 1ππ* state. The protonated structures

150

showed similar geometric and transition features. It is worth to mention that the dihedral

151

angle of C5-C4-C13-O14 took a change from 0.032° to 59.219° in 5fC-P and then made

152

the aldehyde group rotate out of the plane. After excitation to the “bright” 1ππ* state, the

153

internal conversion from the 1ππ* state to the lower 1nπ* may occur as a possible

154

non-radiative deactivation route. Then, correlative deactivation pathways can be

155

successfully obtained by this IC process.

156

The relative energies of corresponding structures have been summarized in Table 2.

157

For 5fC, the S1 states were 86.99 and 88.00 kcal/mol above the S0 states, for neutral and

158

protonated forms, respectively. While for 5caC, they were 94.89 and 103.46 kcal/mol

159

respectively.

160 161

Figure 1. Optimized geometrical parameters for neutral and protonated 5fC and 5caC, calculated

162

at the CAS(8,7)/6-31G(d) level for ground (S0) and excited states (S1). Bond lengths are in Å.



163

Table 2. The relative energies of the stationary states and CIs for singlet neutral and protonated

164

5fC and 5caC in vacuum at CASPT2//CAS(14,10)/6-31G(d) level based on the optimized

165

structures at CAS(8,7)/6-31G(d) level. Energies are in kcal/mol. Neutral

Protonated

Relative energy

Relative energy

(kcal/mol)

(kcal/mol)

5fC-S0

0

0

5fC-S1

86.99

88.00

5fC-BendCI

103.13

116.22

5fC-NHCI

110.04

117.28

5caC-S0

0

0

5caC-S1

94.89

103.46

5caC-BendCI

105.13

94.10

5caC-MI1CI

109.86

124.91

5caC-MI2CI

101.57

91.72

5caC-NHCI

113.05

124.03

Structure

166

3.2. Possible Dissociation Pathways for Neutral and Protonated 5fC and 5caC

167

3.2.1 Singlet state

168

The ring-distortion deactivation and hydrogen dissociation mechanisms have been

169

considered as the effective non-radiative pathways for heterocycles31, 50 and also DNA

170

bases51. To investigate above possible dissociation pathways, firstly, we explored the

171

conical intersections of ring-distortion (noted as BendCI herein) and hydrogen dissociation

172

on NH2 group (noted as NHCI) of 5fC-N, 5fC-P, 5caC-N and 5caC-P at the

173

CAS(8,7)/6-31G(d) level. The optimized structures were presented in Figure 2.

174

The ring-distortion (or ring-pucking) non-radiative decay process is often identified in

175

an internal conversion to the S0 state that facilitated by a CI in out-of-plane deformation

176

coordinate24. In this study, we have located BendCIs of 5fC and 5caC, see Figure 2. The

177

H3 atom of 5caC-N was obviously out of the plane and made the heteroatom ring slightly


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178

twist. And for the protonated forms, in addition to the distortion on H atom, the dihedral

179

angle of H3-C2-C4-C13 changed from -0.01° to 109.44°, which made the carboxyl group

180

turn up evidently. As presented in Table 2, the relative energy of BendCI was 105.13

181

kcal/mol at CASPT2 level for 5caC-N. Compared with the corresponding minimum of S1

182

state, an energy barrier was met (10.24 kcal/mol) when the 5caC-N molecule experienced

183

the ring distortion pathway. While for the protonated state, the predicted energy of BendCI

184

was even below that of the S1 origin and such process was found to be barrierless through

185

linear interpolation in internal coordinate (LIIC) calculations at CASPT2 level in Figure 3.

186

The reoriented conformation of the carboxyl group in 5caC may bring its ground state

187

tautomer, as shown in the Figure S3 and Table S1 with the optimized structures and

188

calculated energies. As compared in the Table S1, the tautomers were calculated to be less

189

stable in both neutral and protonated forms. We also found two kinds of conical

190

intersections involved in the intra-molecular isomer (MICI), see Figure 2. The conical

191

intersection MI1CIs had reorientation of the carboxyl group with a position exchange of

192

O14 and O16. From Table 2, the energies of MI1CIs were 109.86 and 124.91 kcal/mol for

193

5caC-N and 5caC-P, respectively, indicating that both pathways were less energetically

194

favoured than the BendCIs. Moreover, we also found MI2CIs which had obvious ring

195

distortion structures and more importantly, they were only 101.57 kcal/mol and 91.72

196

kcal/mol, which were lower in energies than the BendCIs we discussed above. From the

197

LIIC calculations in Figure 3, we found a small barrier about 6 kcal/mol for

198

5caC-N-MI2CI. On the other hand, it was a barrierless process via 5caC-P-MI2CI.

199

Therefore, the effective intra-molecular isomerism may be another efficient rival

200

non-radiative decay pathways, to which we may pay further attention in our future work.

201

The calculated BendCIs of 5fC were also presented in Figure 2, from the geometric

202

point of view, they were all involved in the distortion of hydrogen atoms in both aromatic

203

ring and the amino groups. The calculated relative energy for BendCI of 5fc-N was 103.13

204

kcal/mol, and it was 116.22 kcal/mol for the protonated form. Both forms will undergo

205

high activation energies and the ring-distortion pathway may not be effective deactivation

206

route for the 5fC system.

207

N-H bond fission is one of the several possible deactivation pathways available to the



208

excited state of many kinds of molecules52. NH-stretching mechanism via a 1NH* repulsive

209

state has been proposed in many heteroatoms53. As shown in Figure 2, the NHCI of 5fC-N

210

displayed a N-H distance of 2.071 Å, and that was much longer of 2.381 Å in the

211

protonated state. Same as the NHCIs of 5caC which displayed longer N-H bond lengths of

212

2.069 and 2.371 Å in the neutral and protonated forms, respectively. In view of energy, all

213

the NHCIs pathways possessed high activation energies as presented in Table 2. For

214

instance, a high activation energy was predicted (23.05 kcal/mol) for the 5fC-N molecule.

215

Such barrier was found to be 18.16 kcal/mol for 5caC-N. In the 5caC-P case, same

216

conclusions have been identified. Besides, we also considered the N6-H8 stretching that

217

may interact with the oxygen of the formyl group and the corresponding CIs have been

218

summarized in Figure S4 and Table S2. From the energetic perspective, it was less

219

possible that the deactivation process took place through the NHCIs, but rather through the

220

ring-pucking, which was energetically preferred mentioned above.


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221 222

Figure 2. The optimized structures of BendCIs, MICIs and NHCIs of 5caC and 5fC at

223

CAS(8,7)/6-31G(d) level. Bond lengths are in Å.



224 225

Figure 3. The energy profiles (using linear interpolations) connecting the excited-state minimum

226

energy geometry to those of the singlet optimized CIs at the CASPT2//CAS(14,10)/6-31G(d)

227

level.

228

3.2.2 Triplet state

229

In addition to the non-radiative deactivation to the ground state, singlet excitons generally

230

may also transfer to the triplet state via intersystem crossing (ISC). Therefore, the deactivation

231

pathways through the triplet states of 5fC and 5caC probably play a determining role and must

232

be considered with care. The optimized geometries of triplet states and the corresponding conical

233

intersections were displayed in Figure 4, and their relative energies were summarized in Table 3.

234

As shown in Figure 4, compared to the 5fC-N-S0 structure, C2=C4 double bond was

235

elongated to a single C-C bond (1.500Å). Such extension broken the conjugated system and

236

planarity of the ring. Specifically, the C2 atom and the formyl group warped away from the ring

237

plane. Same structural characteristics have been found in other triplet states shown in Figure 4.

238

We then optimized two categories of related conical intersections (S1T1CI and S0T1CI series) and

239

summarized their geometrical parameters and energies in Figure 4 and Table 3, respectively. In

240

light of the calculated energies in Table 3, we proposed that ISC processes undergo small

241

activation barriers (about 3~9 kcal/mol) from T1 state to the ground state via S0T1CI series were

242

effective deactivation pathways for both 5fC and 5caC molecules. These CIs were provided with

243

similar structural features of twisted ring and carboxyl or formyl groups. On the other hand, for


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244

the S1T1CI series, almost all of them possessed high energies except for the 5fC-P. The ISC

245

process from the excited singlet state to the triplet state via 5fC-P-S1T1CI was identified as a

246

barrierless process by LIIC calculations in Figure 3. Therefore, we can regard the 5fC-P-S1T1CI

247

as a significant rival radiationless decay for the 5fC-P molecules.

248



Page 14 of 26

249

Figure 4. The optimized structures of triplet states and corresponding conical intersections of

250

neutral and protonated 5fC and 5caC at CAS(8,7)/6-31G(d) level. Bond lengths are in Å.

251

Table 3. The relative energies of the stationary states and CIs for triplet neutral and protonated

252

5fC and 5caC in vacuum at CASPT2//CAS(14,10)/6-31G(d) level based on the optimized

253

structures at CAS(8,7)/6-31G(d) level. Energies are in kcal/mol.

254

Structure

Vacuum Relative Energy (kcal/mol)

5fC-N-T1

77.50

5fC-N-S1T1CI

97.97

5fC-N-S0T1CI

80.92

5fC-P-T1

75.30

5fC-P-S1T1CI

82.01

5fC-P-S0T1CI

84.36

5caC-N-T1

80.38

5caC-N-S1T1CI

101.28

5caC-N-S0T1CI

87.90

5caC-P-T1

80.15

5caC-P-S1T1CI

107.70

5caC-P-S0T1CI

85.47

3.3. Norrish Type I and II Reactions

255

Norrish type II reaction (see Scheme 2) is a photochemical process involved in an

256

intra-molecular γ-hydrogen abstraction of the excited carbonyl compound54. We have located

257

the conical intersections of hydrogen transfer CIs (HTCIs) for 5fC-N and 5fC-P, see Figure

258

5. Such CI resulted from the rotation of formyl group and subsequent intra-molecular H3

259

transfer from the C2 atom to the O14 atom of the formyl group. The formyl groups

260

therefore rotated and turned into the hydroxyl groups with longer C-O bonds of 1.355 and


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261

1.341 Å for 5fC-N and 5fC-P, respectively.

262

From Table 4, we identified a HTCI with hydrogen transfer geometry lying at an

263

energy of 8.59 kcal/mol above and even below the calculated S1 state minimum for 5fC-N

264

and 5fC-P, respectively. However, the LIIC calculation (Figure 3) showed that there were

265

potential-energy barriers for the expected C-H bond-dissociation processes. We optimized

266

the transition states for this type of proton/hydrogen-transfer processes, see structures in

267

Figure 5 and relative energies in Table 4. There were two kinds of transition states

268

involved in the Norrish type II reaction. Firstly, TS1 was the transition state for the rotation

269

of formyl group. Secondly, TS2 was the transition state of the expected C-H stretching

270

which was the rate-determining step. As shown in Table 4, the barriers of TS2 were 33.53

271

kcal/mol and 29.93 kcal/mol for 5fC in neutral and protonated states, respectively. Such

272

high activation energies showed that the hydrogen transfer pathways were lack of

273

competition. In addition, we also investigated the feasibility of such triplet state paths in

274

Figure S5 and Table 3. However, there were still high energy barriers in the

275

proton/hydrogen-transfer processes. NH2

O

N

NH2 H

C

CH

C

N

O

O

N

hv

CH

+

C H

N

O

H

H

5fC

radical pairs

NH2

O

NH2 H

N

O

C

C

N

O

O

N

hv

CH

CH

+

C OH

N

O

H

H

radical pairs

5caC

Norrish Type I NH2 N

NH2 H

C O

O hv

N

CH N

H OH

C O

H

N H

5fC

Norrish Type II

276 277

Scheme 2. The Norrish Type I and Norrish Type II photochemical reaction pathways for 5fC and

278

5caC.



279

Table 4. The relative energies of CIs, intermediates and transition states for neutral and protonated

280

5fC of Norrish Type II reactions in vacuum at CASPT2//CAS(14,10)/6-31G(d) level based on the

281

optimized structures at CAS(8,7)/6-31G(d) level. Energies are in kcal/mol. Neutral

Protonated

Relative energy

Relative energy

(kcal/mol)

(kcal/mol)

5fC-HTCI

95.58

87.19

5fC-HT-TS1

95.03

89.12

5fc-HT-IM

86.32

86.58

5fC-HT-TS2

119.85

116.51

Structure

282 283

Figure 5. The optimized structures of HTCIs, intermediates and transition states of 5fC-N, 5fC-P

284

for Norrish Type II reaction at CAS(8,7)/6-31G(d) level. Bond lengths are in Å.


Page 16 of 26

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285 286

Figure 6. Potential-energy profiles along C-C bond coordinates on the ground and excited states

287

for the neutral (A: 5fC-N, C: 5caC-N) and protonated 5fC (B: 5fC-P, D: 5caC-P). The profiles

288

were drawn from rigid scans at the TDDFT//CAM-B3LYP/6-31G(d) level. Energies are in eV.

289

Bond lengths are in Å.

290

Except the conical intersections we discussed above, we also investigated the

291

photochemical pathway through Norrish type I reaction (see Scheme 2) which was an

292

excited state C-C bond cleavage that initiated by light to produce free radical pairs55. Such

293

C-C bond cleavage reaction can be understood in terms of the rigid scans of

294

potential-energy profiles along C4-C13 at TDDFT//CAM-B3LYP/6-31G(d) level shown in

295

Figure 6. For 5fC-N, 5fC-P and 5caC-N, the

296

adiabatically bound with respect to stretching C-C bond length, but the respective T1 and

297

S0 potentials experienced a CI at long C-C bond length. On the other hand, for 5caC-P,

298

along the Norrish I reaction coordinate, the studied PESs of different excited states were

299

almost parallel to each other. As discussed above that the singlet excitons may transfer to

1

ππ* and


1

nπ* excited states were


Page 18 of 26

300

the triplet state via intersystem crossing (ISC) and from the presented PESs, the

301

intersystem crossing to the ground state can be accessed by motion along a C-C bond

302

fission coordinate.

303

4. The Environmental Effects on the 5fC and 5caC

304

To

study

the

solvent

effects,

the

single

point

energy

calculations

at

305

CASPT2//CAS(14,10)/6-31G(d)/PCM level have been done based on the optimized

306

structures at CAS(8,7)/6-31G(d) level in vacuum, see Table 5.

307

Table 5. Single point energies of 5fC-N, 5fC-P, 5caC-N and 5caC-P calculated at

308

CASPT2//CAS(14,10)/6-31G(d)/PCM

309

CAS(8,7)/6-31G(d) level. Energies are in kcal/mol.

level

based

on

the

structures

Neutral

Protonated

Relative energy

Relative energy

(kcal/mol)

(kcal/mol)

5fC-S0

0

0

5fC-S1

78.61

82.15

5fC-Bend

111.11

124.46

5fC-NHCI

114.62

147.69

5fC-HTCI

92.01

93.98

5fC-HT-TS1

84.25

84.00

5fC-HT-IM

78.05

78.86

5fC-HT-TS2

115.90

111.53

5fC-T1

73.98

72.67

5fC-S1T1CI

94.09

79.71

5fC-S0T1CI

77.33

78.98

5caC-S0

0

0

5caC-S1

100.70

98.10

5caC-BendCI

112.25

76.00

Structure


optimized

at

Page 19 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


5caC-MI1CI

125.25

118.47

5caC-MI2CI

101.00

80.43

5caC-NHCI

102.35

132.99

5caC-T1

83.77

71.33

5caC-S1T1CI

108.28

100.58

5caC-S0T1CI

89.32

77.66

310

311

312

For 5fC, in aqueous solution, the relative energies of S1 states were much lower than

313

those in the gas phase. As summarized in Table 5, they were 78.61 and 82.15 kcal/mol for

314

neutral and protonated forms, respectively. However, the corresponding energies for the

315

most CIs of 5fC have increased in the solution. For instance, the energies for NHCIs are

316

114.62 kcal/mol (solution) vs 110.04 kcal/mol (vacuum) and 147.69 kcal/mol (solution) vs

317

117.28 kcal/mol (vacuum) for 5fC-N and 5fC-P, respectively. As shown in Table 5,

318

introducing the PCM model into the system led to a high energy barrier of over 30

319

kcal/mol for N-H dissociation pathway of both forms. While for HTCI, barriers of 37.85

320

and 32.67 kcal/mol for neutral and protonated forms have been found in the solution. As to

321

the ring-distortion deactivation for 5fC, the barrier through S1 state to BendCI was 32.5

322

kcal/mol in aqueous solution, which was 16.36 kcal/mol higher than that in vacuum for

323

neutral form. On the other hand, the BendCI of the protonated 5fC was 42.31 kcal/mol

324

above the S1 minimum in aqueous solution. Therefore, the solution stabilized the S1 state

325

of 5fC but they rose in CIs and made the non-radiative decay pathway features a sizable

326

energy barrier.

327

The effect of solution on the deactivation mechanism of 5caC was much more

328

complicated. Firstly, for the neutral 5caC, the relative energy of S1 state was predicted to

329

be higher than that in vacuum. Concurrently, the energies of BendCI and MI1CI also went

330

up and brought in approximate barriers compared with those in vacuum. Conversely, the

331

relevant MI2CI and NHCI of neutral 5caC have been stabilized by the solvent. On the

332

other hand, for the 5caC-P, the relative energy of S1 was 98.10 kcal/mol which was a little

333

bit lower than that in vacuum. Besides, relevant CIs were also predicted to be lower to



334

some extent except the NHCI of 5caC-P. As depicted in Table 5, for 5caC, the BendCI and

335

MI2CI were proposed to be the most efficient non-radiative decay route with barrierless

336

threshold energies. For the triplet pathways, in solution, similarly, ISC processes were

337

effective deactivation pathways for both 5fC and 5caC molecules.

338

From above discussions, one may also noticed that the effect of the protonation was

339

important on the deactivation mechanisms. Firstly, from the geometrical view, because of

340

the protonation on the N9 atom, compared to the neutral species, the amino groups of

341

5caC-P-MI1CI and 5fC-P-BendCI turned around due to the positive charge. While, the

342

positive charge also make the N6-H7 distance much longer than that of the neutral ones for

343

NHCIs. Besides, the protonation also changed the energy level order of different excited

344

states. For instance, as shown in Figure 6, after protonation on the 5caC-N, the

345

n(O11)→π* energy profile was lifted up. Such influences may change the electronic

346

properties of conical intersections. For example, the 5caC-N-BendCI was mainly involved

347

in the excitation on the C10=O11, while the 5caC-P-BendCI was mostly involved in the

348

ring and the carboxyl group. Furthermore, from the energetic point of view, the most

349

significant impact was that after protonation, the relative energies for CIs of 5caC like

350

BendCI and MI2CI were reduced somehow, promoting potential non-radiative

351

deactivations. However, in contrary, the protonation on N9 atom lifted up the energy of

352

NHCI which means the N-H dissociation process was somehow influenced by the

353

protonation on N atom nearby the NH2 group.

354

5. Conclusions

355

In summary, recent insights into the multiple consecutive oxidation of epigenetic

356

modifications to the nucleobase cytosine that mediated by TET proteins have shown great

357

potential to promote further understanding of photochemical and photophysical properties

358

of those oxidative products. The main focus of the present work were the systematic

359

analysis of the fundamental excited state photophysical and photochemical processes of

360

5fC and 5caC by using ab initio electronic structure methods etc. Several non-radiative

361

excited state decay pathways following photo excitation via the conical intersections along


Page 20 of 26

Page 21 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


362

the out-of-plane ring deformation (BendCIs), N-H bond fission (NHCIs), hydrogen transfer

363

(HTCIs) and also intra-molecular tautomerism (MI1CIs, MI2CIs) coordinates have been

364

identified by computational approaches. The intersystem crossing (ISC) from S1 state to T1

365

state have been proposed to be possible deactivation pathway for 5fC, while the BendCIs

366

and MI2CIs have been found to be responsible for non-radiative excited state decay

367

processes of 5caC. As well as providing theoretical perspectives of important deactivation

368

mechanisms for those epigenetic markers in DNA, our results also provided important

369

insights into how the introduction of environmental effects such as the solution, the acidic

370

surroundings to the 5fC and 5caC effect the non-radiative deactivation mechanisms. Our

371

computational results for 5fC and 5caC, which have not been addressed so far either

372

experimentally or computationally, may facilitate the understanding of molecular

373

photo-stability of the “new” four bases and thereby providing information for epigenetic

374

studies of their potential involvement in both epigenetic regulation and demethylation

375

pathways.

376

Supporting information

377

The molecular orbitals, the structures and relative energies for intra-molecular isomers,

378

N6H8CIs, HTCIs of the triplet state and so on are available in supporting information.

379

Acknowledgements

380

This work was supported by the National Natural Science Foundation of China

381

(21403064, 21777039), the National Key Research and Development Program of China

382

(2017YFA0207002) and the Fundamental Research Funds for the Central Universities

383

(2017YQ001).

384

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520

55. Wiley, J.; Sons, I., eds. Norrish Type I Reaction, 2010.



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