Computational Approach to Unravel the Role of Hydrogen Bonding in

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Computational Approach to Unravel the Role of Hydrogen Bonding in the Interaction of NAMI-A with DNA Nucleobases and Nucleotides Dharitri Das, Muntazir Saba Khan, Gayatree Barik, Vidya Avasare, and Sourav Pal J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.7b12617 • Publication Date (Web): 16 Aug 2018 Downloaded from http://pubs.acs.org on August 17, 2018

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1 2 3 4 5 6 7 8 9

The Journal of Physical Chemistry

Computational Approach to Unravel the Role of Hydrogen Bonding in the Interaction of NAMI-A with DNA Nucleobases and Nucleotides Dharitri Dasa, Muntazir S Khana, Gayatree Barika, Vidya Avasare*b and Sourav Pal*a§ a

Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400076, India b Department of Chemistry, Sir Parashurambhau College, Pune-411030, India

Abstract

10

Density functional theory method in combination with a continuum solvation model are used

11

to understand the role of hydrogen bonding in interaction of tertiary nitrogen centers of

12

guanine and adenine with monoaqua and diaqua NAMI-A. In case of adenine, interaction of

13

N3 with monoaqua NAMI-A is preferred over N7 and N1 whereas N7 is preferred over N3

14

and N1 in diaqua ruthenium-adenine interaction. In monoaqua and diaqua NAMI-A-guanine

15

interaction N7 site is preferred over N3 site. Here, strength and number of H-bonds play

16

important role in stabilising intermediates and transition states involved in the interaction of

17

NAMI-A and purine bases. Atoms in molecules and Becke surface analysis confirms that

18

structural deformation in the geometry of base pairs of GC and AT dinucleotides occur upon

19

interaction of monoaqua and diaqua NAMI-A. We have also observed that disruption of base

20

pairs in diaqua adducts occurs more than monoaqua adducts. Which suggests that diaqua

21

NAMI-A could have better anticancer agent than monoaqua NAMI-A. This study can be

22

extended to envisage the potential applications of computational studies in the development

23

of new drugs and targeted drug delivery systems.

24

Key Words: NAMI-A, DNA, DFT, AIM, Hydrogen bonding

25 26 27 28 29 30 31 32 1 ACS Paragon Plus Environment

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33

1. Introduction

34

The clinical success of cisplatin in the treatment of numerous cancers stimulated the

35

discovery of the novel transition metal-based drugs which can have better solubility with

36

reduced dose-limiting side effects and resistance phenomena.1-6 The ruthenium complexes

37

have found to be better drug candidates due to their high potential activity as anticancer, anti-

38

metastatic agents and low toxicity. However, their major breakthrough were achieved with

39

the discovery of ruthenium(III) complexes NAMI (Na[trans-RuCl4(dmso-S)(Im)]6) and

40

NAMI-A

41

important role in activating and inhibiting the function (transcription or replication) of DNA

42

nucleobases.11 In the DNA double helix, the N7 atom of purine bases is essentially the known

43

binding site for metal ion coordination, while a simultaneous interaction with the guanine O6

44

atom is also reported.12 It was reported that NAMI-A and Aziruthenium(III) on complexation

45

with DNA changes the overall conformation of DNA oligonucleotides and form a stable

46

adduct with guanine.13

47

In the past few years, computational and experimental methods have made valuable

48

contributions to the collective efforts of deriving a better understanding of how NAMI-A

49

complex reacts with DNA.14-17 Recently, Shukla et al studied the substitution of activated

50

NAMI-A with purine bases through the density functional theory (DFT) study.16 They have

51

explained only the Gibbs free energy profile for the interaction of aqua NAMI-A with the N7

52

site of adenine and guanine. This leaves room for investigating the reactivity of NAMI-A at

53

different coordinating sites of purine bases including N7 site and also to understand the role

54

of hydrogen bonding in stabilising these intermediates. These investigations could help to

55

understand the factors contributing towards the higher activation energy barrier of a particular

56

site of purine bases and alterations in the thermodynamic stability, mechanical and functional

57

properties of the DNA. Towards this, we have investigated the Ru―N/Ru―O bond

58

formation between aqua NAMI-A and adenine/guanine with respect to the change in the

59

kinetic behaviour of the corresponding reactants and transition states. Here, we have

60

examined the various factors responsible for the structural deformation of DNA upon NAMI-

61

A coordination. We have performed the systematic analyses of the geometries, reaction-

62

energy pathways, various bonding parameters such as bond length, electron densities,

63

hydrogen bond energy and π-stacking energy of NAMI-A with DNA nucleobases and

64

nucleotides in an aqueous medium. All the possible geometrical variations in the structure of

65

intermediates and transition states were considered for the present study. All computational

([ImH][trans-RuCl4(dmso-S)(Im)]).7-10 Ruthenium(III)

complexes

play

an

2 ACS Paragon Plus Environment

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66

analyses were performed using the mono and diaqua forms of NAMI-A than the parental

67

form (chloro form of NAMI-A) because NAMI-A readily undergoes hydrolysis at

68

physiological conditions (pH=7.4).18 The computational studies on the reactivity of the

69

monoaqua species [trans-RuCl4(1H-imidazole)(dmso-S)] or diaqua species [trans-RuCl4(1H

70

imidazole)(dmso-S)]+ of NAMI-A have seldom reports. Here, the mechanistic investigations

71

of the coordination of NAMI-A with the nucleobases using monoaqua and diaqua species

72

have been studied. These findings can be useful to understand the reactivity of NAMI-A

73

towards DNA bases as well as to know a process of the loss of stability of DNA base pair

74

upon NAMI-A interactions.

75

2. Computational Details

76

GAUSSIAN09 program package19 is employed to carry out density functional theory (DFT)

77

calculations on interaction mechanism of mono and diaqua forms of NAMI-A with DNA

78

purine bases as well as double stranded DNA dinucleotide. Geometry optimization of all

79

stationary points are performed using meta-GGA hybrid M06 functional with triple zeta split

80

valence, polarized and diffuse 6-311++G(d,p) basis set for all atoms except ruthenium.20, 21

81

The LANL2DZ basis set comprising of an effective core potential (ECP) for 28 core

82

electrons and a double-ζ valence basis set for 16 valence electrons is used for ruthenium.22 A

83

vibrational analysis at the same level of theory has been performed to ensure that optimized

84

structures are local minima or transition state i.e. all positive frequencies ensuring minimal

85

state and one negative frequency ensuring first-order transition state. The transition states

86

have also been confirmed by intrinsic reaction coordinate (IRC) calculations.23,24 All

87

calculations presented in this work are evaluated in the presence of water (with dielectric

88

constant 78.39) using implicit solvation model conductor-like polarizable continuum model

89

(CPCM) at 298.15 K temperature and 1 atm pressure.25 Here, we have used Pople’s 6-

90

31G(d,p) basis set and M06 functional with dispersion correction for geometry optimization

91

of interacting NAMI-A with AT and GC dinucleotides in the gas phase.22 Also, meta-GGA

92

hybrid M06 functional has been used because it accounts for noncovalent interactions in

93

transition metal systems with 27% of the HF exchange which helps to reduce self-interaction

94

error.26-28 The binding energies for the mono and diaqua NAMI-A with DNA bases, double

95

stranded DNA dinucleotide have been corrected for the basis set superposition error (BSSE),

96

through the counterpoise method of Boys and Bernardi.29 Wave function files are generated

97

using single point calculations on the Gaussian output files at M06/(LANL2DZ+6-

98

311++G(d,p) level of theory to perform atoms in molecules (AIM)30 and Becke surface31 3 ACS Paragon Plus Environment


99

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analysis of the electron density distribution. The topology and Becke surface analysis are

100

evaluated using the open source Multiwfn package.32

101

Activation energy ( Ea ) is obtained during rate constant ( k ) calculation using two parametric

102

Arrhenius equation with Kinetic and Statistical Thermodynamical Package (KiSThelP)33

103

The two parametric Arrhenius equation can be expressed as34

104

 E  k = A exp − a   RT 

105

where A is the prefactor.

106 107

3. Results and Discussion

108

3.1. Reaction mechanisms

109

It has been reported that N1, N3 and N7 sites in adenine (A) and N7 and N3 sites in guanine

110

(G) are the most reactive coordination sites for metal binding nucleobases.35,36 Here, we have

111

investigated the complexation mechanism of NAMI-A with DNA purine bases through all

112

possible coordination sites. In order to nullify the interference of steric and phosphoribose

113

bridges effects, all the stationary points that are characterized in the mechanism are calculated

114

in the absence of the surrounding DNA bases and backbone as per literature reports.5,6

115

Therefore, the absolute energies obtained may be deviated slightly from the actual results. To

116

test the accuracy of our computational setup, we have calculated the structural and energetic

117

properties of NAMI-A at the M06, B3LYP with dispersion correction and MP2 level and

118

results obtained from both methods are similar (Table S1 and S2 and Figure S1).37

119

3.1.1. Significance of hydrogen bonding towards interaction of DNA purine bases with

120

monoaqua NAMI-A

121

3.1.1.1. Structural characterization of interaction of N3 of guanine (G) with monoaqua

122

NAMI-A

123

In the interaction reaction of monoaqua NAMI-A with guanine, intermediate I1G is obtained

124

when monoaqua NAMI-A interacts at the N3 site of guanine (N3G) through pathway IG

125

(Scheme 1). It has been well documented that the intermolecular hydrogen bonds play an


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126

important role in stabilizing activated cisplatin complexes during their interaction with

127

nucleobases.5

128 CH3

H3C H3C O Cl

CH3 Pathway IG

S

Cl

Ru

Y NH2

Ru N

Cl

NH1

X N3

Cl

S O

O

N7

NH

NH

O

Y + 1HN X H2N

Imi R

N3 Guanine

H N

CH3

H3C Pathway IIG

Cl

O S

N7

Ru X

Cl

N

Monoaqua NAMI-A; X = OH2 and Y= Cl Diaqua NAMI-A; X, Y = OH2

R1G; X = OH2, Y= Cl R3G; X, Y = OH2

Y

Cl

CH3 Cl

O S

NH2

Cl

NH

Cl

129 130

N

CH3

H3C Cl

O S

Y

X

Ru

NH2 N3

O

TS2G; X = OH2, Y= Cl TS4G; X, Y= OH2

X

Ru

NH1

N H

O

CH3 Y

N

NH2

N3

N7

NH1

N3

NH TS1G; X=OH2, Y = Cl TS3G; X, Y = OH2

Cl

Y

Ru

NH N7

O S

O

CH3

O S

X

N

H3C

N H

X

Y

Ru Cl

NH1

R2G; X = OH2, Y = Cl R4G; X, Y = OH2

H3C H3C

N7

NH

NH2

N3

Cl NH1

O N7 N NH H I1G; X = OH2, Y = Cl I3G; X,Y = OH2

N

N7

NH

N H

NH2

N3

NH1 O

I2G; X = OH2, Y = Cl I4G; XY= OH2

Scheme 1. Interaction of monoaqua and diaqua NAMI-A with guanine

131

However, the electron density and electron density mapping study could provide better

132

understanding of the role of hydrogen bonding in stabilizing these active intermediates. In the

133

intermediate R1G of pathway IG, we have observed that there is a strong association of

134

Ru―OH2 (2.15 Å) and Ru―N3G (3.88 Å) interaction is very weak (Figure 1 and Table S3).

135 5 ACS Paragon Plus Environment


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136 137

R1G

TS1G

I1G

138 139

R2G

TS2G

I2G

140 141

Figure 1. Optimized structures for the species involved in the monoaqua NAMI-A-adenine

142

and guanine interaction obtained at M06/(LanL2DZ+6-311++G(d,p) level.

143

In the intermediate R1G, water ligand of NAMI-A is interacted with guanine through two

144

strong hydrogen bonds, H2OH1….N3G (1.74 Å) and H2O….HNG (2.39Å) which facilitates

145

the displacement of water ligand. This observation is also verified by electron density (ρ) at

146

the bond critical point (BCP) for H2OH1….N3G bond (0.045 a.u.) and H2O….HNG (0.011

147

a.u.) which is consistent with H-bond distances. Here, water ligand is also strongly interacted

148

with DMSO ligand through H-bond, H1OH2….O(DMSO) (1.98 Å; ρ= 0.024 a.u.). The same

149

water ligand is weakly interacted with N3G, H1OH2….N3G (3.35 Å). Thus, N3G is interacted

150

with both hydrogen of water. A pentagonal bipyramidal transition state TS1G is observed 6 ACS Paragon Plus Environment

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151

between NAMI-A and guanine which is confirmed by the presence of one imaginary

152

frequency. At the transition state TS1G, the Ru―OH2 (ρ=0.032 a.u.) bond is broken and a

153

new Ru―N3G bond (ρ=0.018 a. u.) is formed. Which is clearly observed through the change

154

in the bond distance of Ru―N3G bond from 3.88 Å in R1G to 2.92 Å in TS1G and also

155

Ru―OH2 distance increases from 2.15Å to 2.56Å. Further, H-bond distances of

156

H2OH1….N3G and H2O…HNG bonds increases from 1.74 Å and 2.39 Å in R1G to 3.38 Å

157

and 3.12Å and N(imidazole)….HNG bond decreases in TS1G (2.64 Å) as compared to R1G

158

(3.60Å). Guanine approaching towards ruthenium coordination centre of NAMI-A and water

159

moving away from ruthenium coordination site are clearly seen in the transition state TS1G.

160

Three weak H-bonds, H2OH1….N3G (3.38 Å), H1OH2….N3G (3.28 Å) and H2O…HNG

161

(3.12 Å) between nitrogen of guanine and water ligand of NAMI-A along with a strong H-

162

bond, H1OH2….O(DMSO) (1.89 Å, ρ = 0.029 a. u.) between water and DMSO ligand of

163

NAMI-A attributes to the stability of transition state TS1G. The intermediate I1G is formed

164

from intermediate R1G through transition state TS1G with activation energy barrier of 22.5

165

kcal/mol (Figure 2 and Table 1). In the intermediate I1G, N3G is coordinated with the Ru3+

166

by forming Ru―N3G bond (2.19 Å; ρ = 0.072 a. u.) via displacement of water ligand from

167

NAMI-A. This results into a formation of strong H-bond between guanine and DMSO

168

oxygen of NAMI-A (H2NH1G….O(DMSO = 1.75 Å, ρ = 0.039 a. u.). In the intermediate I1G

169

where H-bond distance between water ligand and N3G is found to be H2OH1….N3G = 5.08

170

Å and H1OH2….N3G = 5.73 Å, which indicates that water is no longer associated with N3G

171

as seen in intermediate R1G. The overall mechanism suggests that the ligand substitution

172

reaction occurs via an interchange mechanism with a dissociative character.

173

Table 1. Change in enthalpy ( H ), Gibbs free energy ( G ) and activation barrier ( Ea ) of

174

each step of reaction pathways and BSSE corrected interaction energy of reactants calculated

175

at M06/(LanL2DZ+6-311+G(d,p)) level. Values are in kcal/mol.

H

G

Ea

R1G→I1G

-0.2

-1.8

22.5

R2G→I2G

-2.1

-2.6

R1A→I1A

-2.1

R2A→I2A

E

BSSE

R1G

-24.1

2.96

19.8

R2G

-16.8

2.46

-4.0

25.2

R1A

-21.1

2.19

-4.6

-4.8

23.8

R2A

-23.4

2.27

R3A→I3A

-2.8

-4.1

28.4

R3A

-21.4

2.77

R3G→I3G

-1.5

-1.8

20.2

R3G

-17.2

2.66 7

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R4G→I4G

-12.3

-12.7

14.2

R4G

-15.2

1.99

R4A→I4A

-1.4

-1.9

21.0

R4A

-14.9

1.67

R5A→P5A

-4.3

-3.4

21.5

R5A

-16.3

1.74

R6A→P6A

-2.9

-3.9

20.7

R6A

-16.9

2.08

176 177

3.1.1.2.Structural characterization of interaction of N7G with monoaqua NAMI-A

178

The interaction mechanism of monoaqua NAMI-A with the N7G is presented in pathway IIG

179

(Scheme 1). Here, in the intermediate R2G, ruthenium shows weak coordination with N7G

180

(Ru―N7G = 3.92 Å) and strong coordination with water ligand (Ru―OH2=2.12 Å) (Figure

181

1 and Table S3). The N7G forms a strong H-bond with water ligand of NAMI-A

182

(H2OH1….N7G=1.69 Å; ρ=0.051 a.u.) and a weak H-bond with other hydrogen of water

183

ligand (H1OH2….N7G = 3.25Å). This water ligand also connects to DMSO through a strong

184

H-bond, H1OH2….O(DMSO) ( 2.06 Å; ρ= 0.021 a.u.). The basis set superposition error

185

(BSSE) corrected interaction energy ( E ) show that energy difference between the

186

intermediates R1G (-24.1 kcal/mol) and R2G (-16.8 kcal/mol) is 7.3 kcal/mol (Table1).

187

However, as described above, the intermediate R1G is stabilised with three strong and one

188

weak hydrogen bonds. While two strong and one weak hydrogen bonds stabilize R2G.

189

Hence, E and H-bond interactions show that less energy will be required for the conversion

190

of intermediate R2G to intermediate I2G than the conversion of R1G into I1G. The

191

intermediate R2G is converted into I2G through the transition state TS2G. Transition state

192

TS2G clearly shows the breaking of Ru―OH2 (3.35 Å) bond and a formation of new bond

193

between ruthenium and N7G (Ru―N7G=2.99 Å). The transition state TS2G is associated

194

with one strong H-bond, H2OH1….N7G (1.90Å; ρ= 0.031 a.u.) along with three weak H-

195

bonds, H1OH2….N7G (3.29 Å), H2OH1….O(DMSO) (3.63 Å) and H1OH2….O(DMSO) (3.39

196

Å). Transition state TS2G is followed by the formation of intermediate I2G with activation

197

energy barrier of 19.8 kcal/mol (Figure 2). In the intermediates I2G, guanine replaces water

198

ligand and gets coordinated with ruthenium through N7G (Ru―N7G =2.12Å; ρ= 0.086 a.u).

199

However, N7G remains connected with water ligand of NAMI-A and forms a moderate H-

200

bond with bond length 3.06Å.

201

3.1.1.2.Energetics analysis

202

The difference in activation energy barrier for the conversion of R1G→I1G (22.5 kcal/mol)

203

and R2G→I2G (19.8 kcal/mol) demonstrates that ruthenium-guanine coordination through 8 ACS Paragon Plus Environment

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204

N7G is ~ 3.1 times faster than N3G. The presence of maximum number of hydrogen bonds in

205

TS2G than TS1G make transition state TS2G more stable than transition state TS1G, hence

206

decrease in activation energy barrier for the conversion of R2G→I2G (Figure 2). In the

207

transition state TS1G, water ligand of NAMI-A interacts with DMSO through H-bond

208

(H1OH2….O(DMSO) =1.89 Å; ρ= 0.029 a.u.) which indicates the association of water ligand

209

with ruthenium centre in TS1G while as in TS2G no such hydrogen bonding is observed

210

which results into slow dissociation of water ligand in TS1G and increase of the activation

211

energy. The overall observation suggests that hydrogen bonding plays significant role in

212

stabilising intermediates and transition states during the interaction reaction of NAMI-A with

213

guanine.

214 215

Figure 2. Relative Gibbs free energy (kcal/mol) profile diagram for interaction of

216

monoaqua NAMI-A with N3 and N7 of guanine. Activation barrier (kcal/mol) are

217

shown in the squares along the reaction path.

218

3.1.1.3. Structural characterization of interaction of N1A with monoaqua NAMI-A

219

We have discussed the interaction mechanism of monoaqua NAMI-A with the N1 of adenine

220

in Pathway IA (Scheme 2). In this pathway IA, the intermediate R1A is stabilised by strong 9 ACS Paragon Plus Environment


Page 10 of 37

221

Ru―OH2 bond (2.12 Å; ρ= 0.072 a.u.)), weak interaction of Ru―N1A (4.05Å), a strong H-

222

bond with water ligand (H2OH1….N1A= 1.71 Å, ρ= 0.050 a.u.) and two weak H-bonds

223

(NH…..N3A = 3.72 Å, H2O…...H2NH1=3.42 Å) (Table S4). Here, a strong interaction is also

224

observed between hydrogen of water and oxygen of DMSO ligand (H1OH2….O(DMSO) =

225

2.09 Å; ρ= 0.019 a.u.). Further conversion of R1A to I1A proceeds through transition state

226

TS1A. Here, in transition state TS1A, the parallel bond formation of Ru―N1A (2.91 Å,

227

ρ=0.019 a.u.) and departure of Ru―OH2 bond (2.47 Å, ρ=0.038 a. u.) are observed; which

228

clearly establishes the interchange dissociative mechanism. The transition state TS1A

229

consists of a strong H-bond,


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CH3

H3C Cl Pathway IA

S O

Y

Pathway IIIA

+

Ru Cl

N7

HN

NH2

N3

X

N1 Adenine

Imi R

Monoaqua NAMI-A; X = OH2 and Y= Cl Diaqua NAMI-A; X, Y = OH2

Pathway IIA

H3C O Cl

CH3

3HC

S Cl

Y Ru

NH

N H2N

Cl

O X Cl

N1

Cl

Cl X

Ru Cl

N H

230 231

NH

N H2N

N7

I1A; X = OH2, Y = Cl I4A; X,Y = OH2

Y

Cl

N

X H2N N7

NH N H

N1

S

Cl

X

N NH

Cl

H N N3

N3 H2O

CH3

H3C

Y

N1

TS3A; X = OH2, Y=Cl TS6A; X, Y= OH2

CH3

Ru

N3 N1

O S

NH2

O

N3

CH3

N7

NH

N H

Ru

N3

N

N1

R3A; X = OH2, Y = Cl R6A; X, Y = OH2

X H N

H2N N7

NH

Cl

Y

H3C

Y

N

H3C

TS2A; X = OH2, Y=Cl TS5A; X, Y=OH2

CH3

Y

X

N1

S

N7

TS1A; X= OH2, Y=Cl TS4A; X, Y=OH2

O S

Cl

CH3

NH

NH H N 2

H3C

N3

Ru N3

N

O S

N7

Cl

Y

H N

NH2 R2A; X = OH2, Y= Cl R5A; X, Y= OH2

Ru Cl

X

N

H3C

CH3

Ru

NH

CH3

O S

Cl

Cl

N7

R1A; X = OH2, Y = Cl R4A; X, Y= OH2

H3C

X

Ru

X N1 NH

H3C

O S

N3

Cl

CH3

O S

Y

Ru N7

N1

Cl

N

I2A; X = OH2, Y = Cl I5A; X, Y = OH2

H2N N7

NH N H

NH2

X

N1 N3

I3A;X = OH2, Y = Cl I6A; X, Y = OH2

Scheme 2. Interaction of monoaqua and diaqua NAMI-A with adenine 11 ACS Paragon Plus Environment


Page 12 of 37

232

H2OH1…..O(DMSO) (1.87Å; ρ=0.031 a.u.), three moderate, H1OH2…..O(DMSO) (3.11Å),

233

N(imidazole)…..H1NH2A (2.58Å) and H2O…..H1NH2A (2.84

234

H1OH2…..NH2A (3.33 Å), H2O…..H2NH1A (3.93 Å) H-bonds responsible for additional

235

stability. The transition state TS1A further converts into I1A with an activation energy

236

barrier 25.2 kcal/mol (Figure 3). The high electron density at Ru―N1A bond (2.17 Å, ρ =

237

0.079 a. u.) is an indicative of strong bond formation between these two in the intermediate

238

I1A. The intermediate I1A possesses two strong H2O…..HNA (2.03 Å; ρ = 0.022 a. u.),

239

H2OH1…..N3A

240

N(imidazole)…..H2NH1A (2.57 Å) H-bond make this I1A intermediate more stable like

241

intermediate RIG. Unlike R1G, in the intermediate I1A, water ligand is completely

242

dissociated from NAMI-A (Ru―OH2 =7.12 Å).

(2.04

Å;

ρ

=

0.023

a.u.)

bonds,

one

Å) and two weak

moderately

strong

243 244


245

monoaqua NAMI-A with N1A, N3A and N7 A. Activation barrier (kcal/mol) are shown

246

in the squares along the reaction path.

247



Page 13 of 37 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


248

Pathway IIA, represents the interaction mechanism of monoaqua NAMI-A with the N3 of

249

adenine (Scheme 2). Here, the intermediate R2A shows a weak coordination between Ru3+

250

and N3 of incoming adenine (Ru―N3A = 4.15 Å) (Table S4). The presence of two strong H-

251

bonds, H2OH1…..N3A (1.71Å; ρ=0.049 a.u.) and H1OH2…..O(DMSO) (1.99 Å; ρ=0.024

252

a.u.) attribute towards the stability of the intermediate R2A. A parallel Ru―OH2 bond

253

cleavage (2.47Å) and Ru―N3A (2.63Å) bond formation are observed in the transition state

254

TS2A. Here, the presence of one strong (H2OH1…..O(DMSO)=1.91Å; ρ=0.029a.u.), five

255

moderate (H1OH2…..O(DMSO)=3.04Å, N(imidazole)…..HNA = 3.03 Å, H2O…..NHA=2.70Å,

256

H1OH2…..NHA = 3.15Å and H2OH1…..N3A=3.23Å) and three weak (HN(imidazole)….HNA

257

=4.04 Å, H2OH1…..NHA=3.98 Å and H1OH2…..N3A= 3.43 Å) H-bonds stabilize the

258

transition states TS2A. The intermediate I2A is obtained through transition state TS2A from

259

the intermediate R2A with an activation energy barrier of 23.8 kcal/mol. In the intermediate

260

I2A, water ligand is displaced from the ruthenium centre and adenine gets coordinated with

261

Ru3+ through N3 (Ru―N3A = 2.12 Å; ρ= 0.088 a.u). However, N3G remains connected with

262

water ligand through both the hydrogen atoms with moderate to weak H-bonds

263

(H2OH1…..N3A = 3.23 Å, H1OH2…..N3A = 3.64 Å).

264


265

In pathway III, the intermediate R3A shows a strong association of Ru―OH2 (2.14 Å) and a

266

weak Ru―N7A (3.97 Å) bonds (Scheme 2). Water ligand of NAMI-A remains interacted

267

with adenine through two strong H-bonds, H2OH1….N7A (1.70 Å; ρ= 0.050 a.u.) and

268

H2O….H1NH2A (2.09Å; ρ= 0.018 a.u.) in the intermediate R3A.

269

hydrogens of water ligand is strongly interacted with oxygen of DMSO ligand

270

(H1OH2….O(DMSO) = 2.02Å and ρ= 0.021 a.u.) while the another hydrogen atom is weakly

271

interacted with oxygen of DMSO, (H1OH2….O(DMSO) = 3.56 Å) are responsible for the

272

slow displacement of water ligand from ruthenium center. The presence of one imaginary

273

frequency confirms the formation of transition state TS3A between NAMI-A and adenine

274

(Table S4).Transition state TS3A involves the cleavage of Ru―OH2 (ρ=0.032 a.u.) bond

275

with the simultaneous formation of Ru―N7A (ρ=0.025 a. u.) bond. This is also observed

276

through the change in the bond distances, Ru―N7A bond distance is reduces from 3.97 Å in

277

R3A to 2.75 Å in TS3A while as Ru―H2O distance increases from 2.14 Å to 2.57 Å. Thus

278

transition state TS3A clarifies the movement of adenine towards ruthenium of NAMI-A,

279

whereas water is moving away from ruthenium. An activation energy barrier of 28.4 kcal/mol

280

is obtained for the conversion of intermediate R3A into intermediate I3A. In the intermediate

Here also, one of



Page 14 of 37

281

I3A, bond between water ligand and ruthenium disappears (Ru―OH2 =4.31 Å) and the bond

282

between N7G with ruthenium gets strengthened (Ru―N7A =2.14Å; ρ = 0.083 a. u.). We

283

have also observed a strong H-bond between adenine and -NH of imidazole of NAMI-A

284

(N(imidazole)

285

(N(imidazole)….H2NH1=

286

HN(imidazole)….H2NH1A= 3.99 Å) which confirms the formation of a stable intermediate

287

I3A. To understand the interaction reactions under physiological conditions, the model study

288

on interaction of N7A with NAMI-A at 310.15 K was performed and we observed that the

289

activation energy of N7A and NAMI-A interactions remains unchanged at this temperature.

290

This finding endorses that computational results obtained at 298.15 K are valid under

291

physiological conditions too.

292

3.1.1.5. Energetics analysis

293

BSSE corrected interaction energy ( E ) for the intermediates R1A (-21.1 kcal/mol), R2A (-

294

23.4 kcal/mol) and R3A (-21.4 kcal/mol) shows that all the intermediates are almost equally

295

reactive towards the interaction reaction (Table1). The intermediate R1A is stabilised with

296

two strong and two weak hydrogen bonds, as described above. Whereas two strong and four

297

weak hydrogen bonds in R2A and three strong and one weak hydrogen bonds in R3A

298

stabilize the intermediates. However, hydrogen bonds in R3A is associated with maximum

299

electron density (ρ= 0.089 a.u.) as compared to R1A (ρ= 0.069 a.u.) and R2A (ρ= 0.073 a.u).

300

BSSE energy and H-bonding interactions show that intermediate R3A is more stable than

301

R1A and R2A.

302

The lower in activation energy in TS2A is due to the presence of nine H-bonds whereas in

303

TS1A seven hydrogen bonds are observed (Table S4). The more hydrogen bonding network

304

stabilizes the TS2A to a greater extent than TS1A and hence, it makes the interaction reaction

305

of NAMI-A faster with N3A. The computational study of protonation of guanine and adenine

306

performed by Russo and co-workers suggested that in guanine, N7 is the most preferred site

307

for the protonation reaction over N3 and O6 which is in good agreement with the metallation

308

study.38According to their findings, N1 of adenine is the most preferred protonation site over

309

N3 and N7 and hence it is expected that N1 should also be the favourable site for NAMI-A

310

interactions. In case of guanine, the N7-TS2G shows more H-bonds than N3 and O6 while as

311

in adenine N3 shows more H-bonds in N3-TS2A than N1 and N7. Here, H-bonding attributes

312

to the difference in reactivities of adenine and guanine nitrogen sites towards NAMI-A. This

….H1NH2A=

2.55 Å, ρ = 0.011 a. u.) and multiple weak H-bonds 3.85

Å,

HN(imidazole)….H1NH2A=

3.59

Å,


Page 15 of 37 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


313

further validates the significance of the number of H-bonds in stabilising the interactions of

314

nitrogen sites towards NAMI-A interaction reaction.

315 316 317

3.1.2. Significance of hydrogen bonding towards interaction of DNA purine bases with

318

diaqua NAMI-A

319

3.1.2.1. Structural characterization of interaction of N3G with diaqua NAMI-A

320

In pathway IIIG, the intermediate R1A is associated with strong Ru―OH2 bond (2.12 Å, ρ=

321

0.076 a.u), weak Ru―N3G (3.92Å) bond (Scheme 1). However, the presence of three strong

322

bonds, H2OH1(1st water ligand)….N3G (1.75Å; ρ= 0.044 a.u.), H1OH2….O(DMSO) (2.02Å;

323

ρ= 0.023a.u.), H2’OH1’(2nd water ligand )….NH (1.89Å; ρ = 0.032 a.u.), four moderate H-

324

bonds, H2OH1….NH2 (2.91 Å), H2O’….H1NH2 (3.07 Å), NH….N7G (3.08 Å), H2OH1….NH=

325

3.15 Å) and six weak H-bonds (H1OH2….N3G (3.36 Å), H2OH1….O(DMSO) (3.59Å),

326

H1’OH2’….NH2 (3.96 Å), H2O….H1NH2 (3.34 Å), H2O’….H2NH1(3.39 Å), H2O’….HN (3.50

327

Å) make the intermediate R3G a stable structure (Table S5). The intermediate R3G is

328

converted into intermediate I3G through a transition state TS3G. In TS3G, Ru―N3G

329

distance decreases from 3.92 Å (in R3G) to 2.14 Å, which represents the ruthenium guanine

330

bond formation. Simultaneously, water ligand moves from the reaction centre with increase

331

in Ru―OH2 distance from 2.12 (in R3G) to 4.19 Å, indicating a dissociative character of the

332

transition state. Additional stability to the transition state TS3G is rendered by two strong H-

333

bonds, H2OH1….O(DMSO) (1.85Å; ρ= 0.029 a.u.), H2O….H1NH2G (2.30 Å; ρ= 0.014 a.u.),

334

two moderate, H2OH1….N3G (3.02 Å), H1OH2….O(DMSO) (3.29Å) and N(imidazole)….HN

335

(2.63Å) and two weak, H2OH2….N3G (3.92 Å), H2O’….H2NH1G (3.66 Å) H-bonds. The

336

transition state TS3G further leads to the formation of intermediate I3G with an activation

337

energy barrier 20.2 kcal/mol. In I3G intermediate structure, the incoming N3G forms a bond

338

with ruthenium Ru―N3G (2.15Å, ρ= 0.084 a.u) by replacing the water ligand Ru―H2O

339

(4.57 Å). Here, the intermediate I3G possesses two strong H-bonds, H2O….NHG (2.02 Å, ρ=

340

0.021 a.u.) and H2NH1….O(DMSO) (1.89 Å, ρ= 0.029 a.u.) and three weak H-bonds

341

(H2OH1….NHG = 3.47 Å, H1OH2….NHG = 3.45 Å and H1NH2….O(DMSO)= 3.46 Å)

342

contribute towards the stability of it. The complete displacement of water ligand from NAMI-

343

A is observed in the intermediate I3G as Ru―OH2 bond distance increases from 2.12 Å to

344

4.57 Å. 15 ACS Paragon Plus Environment


Page 16 of 37

345

3.1.2.2. Structural characterization of interaction of N7G with diaqua NAMI-A

346

In the Pathway IVG, the intermediate R4G shows a weak coordination between Ru+3 and

347

N7G (Ru―N7G = 3.98 Å) (Scheme 1). In the intermediate R4G, a strong H-bond is

348

observed between N7G and one of the hydrogens of water ligand (H2OH1’….N7G (1.69 Å;

349

ρ=0.051 a.u.). The same N7G makes a moderate H-bond with other hydrogen of water ligand

350

(H1OH2’….N7G (2.87Å). Here, we have also seen two H-bonds between O6 of guanine and

351

water ligand of NAMI-A, H2OH1….O6G (2.74 Å) H1’OH2’….O6G (1.87Å; ρ=0.030 a.u.).

352

Substitution of water ligand by N7G to form intermediate I4G from intermediate R4G

353

through the transition state TS4G. In transition state TS4G, a simultaneous cleavage of

354

Ru―OH2 (2.56 Å) and a formation Ru―N7G (2.59 Å) bond is observed and hence, it

355

follows an interchange dissociative mechanism. In the transition state structure TS4G, we

356

observed

357

H2’OH1’….N7G (2.72Å), H1’OH2’….N7G(3.64 Å), H2OH1….N7G (2.55Å), H1OH2….N7G

358

(3.55Å), H2OH1….N(imidazole) (3.87 Å) and H1OH2….N(imidazole) (3.31 Å) which render

359

the stability to the structure. The pseudo-octahedral geometry of intermediate I4G which is

360

obtained through TS4G (14.2 kcal/mol) is observed. In this intermediate water ligand is

361

completely exchanged by N7G and N7G forms a bond with ruthenium at 2.10 Å. Although,

362

one water ligand moves away from ruthenium coordination centre in I4G, still one of the

363

hydrogen of water remains connected with guanine through a weak H-bond (H2OH1….N7G

364

=3.27 Å). However, the second water ligand of NAMI-A forms two strong

365

(H2’OH1’….O6G= 1.64 Å; ρ= 0.049 a.u., H2’OH1’….N7G= 2.91 Å; ρ= 0.017 a.u) and one

366

weak (H1’OH2’….O6G= 3.20 Å) H-bonds with guanine in the intermediate I4G contribute to

367

the stability.

368


369

BSSE corrected interaction energy ( E ) is obtained for the intermediates R3G (-17.2

370

kcal/mol) and R4G (-15.2 kcal/mol) however, R4G results into the more stable transition

371

states than R3G (Table1). The activation energy barriers for the formation of intermediates

372

I3G and I4G are observed to be 20.2 kcal/mol and 14.2 kcal/mol ( Ea = 14.8 kcal/mol at

373

310.15K) respectively (Figure 4). As discussed above, when water and DMSO bond is

374

stronger than expected then dissociation of Ru―OH2 bond is very slow, hence energy

375

associated with such intermediates and transition states is expected to be high. In the case of

376

transition state TS3G, the H-bond between water and DMSO ligand of NAMI-A is stronger

eight

H-bonds,

H2’OH1’….O6G

(1.64

Å),

H1’OH2’….O6G

(3.14Å),


Page 17 of 37 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


377

(H2OH1….O(DMSO)=1.85Å,

H1OH2….O(DMSO)=3.29Å)

378

(H2OH1….O(DMSO)=3.32Å, H1OH2….O(DMSO)= 3.85 Å) which make

379

preferred transition state. From BSSE corrected interaction energy results, we expected an

380

equal reactivity of N3G and N7G towards NAMI-A but TS4G is better stabilized with eight

381

H-bonds as compared to TS3G which is stabilized by five H-bonds. Overall discussion

382

shows that activation energy barrier of transition state TS3G is higher than TS4G and hence

383

faster interaction reaction of NAMI-A with N7G is observed.

than

TS4G TS3G

less

384 385


386

diaqua NAMI-A with N3G and N7G. Activation barrier (kcal/mol) are shown in the

387

squares along the reaction path.

388

3.1.2.4. Structural characterization of interaction of N1A with diaqua NAMI-A

389

In the pathway IA, the intermediate R4A (Scheme 2) is associated with a weak coordination

390

of Ru―N1A (4.20Å) along with three strong H-bonds, H1OH2…..O(DMSO) (1.99 Å; ρ=

391

0.024 a. u.) H2’OH1’…..NH2A (1.86 Å; ρ = 0.035 a. u.) H2OH1 …..N1A (1.70 Å; ρ= 0.051

392

a.u.), four moderate

393

N(imidazole)…..H1NH2A (2.63 Å), HN(imidazole)…..H1NH2A (3.08Å) and four weak H-

394

bonds, H2OH1…..O(DMSO) (3.48 Å), H1’OH2’…..NH2A (3.39 Å), H2O’…..H2NH1A (3.46 Å,

H-bonds,

H1OH2…..N1A(3.13Å) H2O’…..H1NH2A

(3.06 Å),



Page 18 of 37

395

N(imidazole)…..H2NH1A (3.96 Å) (Table S6). The intermediate R4A is converted into I4A

396

via transition state TS4A. Here, in transition state TS4A, interchange dissociative mechanism

397

is clearly observed as there is the parallel bond formation and cleavage of Ru―N1A (2.63 Å,

398

ρ=0.033 a.u.) and Ru―OH2 bonds (2.48 Å, ρ=0.038 a. u.) respectively. The transition state

399

TS4A

400

N(imidazole)…..H1NH2A (2.26 Å; ρ=0.015a.u.), two moderate, H2OH1…..O(DMSO) (3.17

401

Å),

402

N(imidazole)…..H2NH1A (3.86 Å) and HN(imidazole)…..H1NH2A ( 3.26 Å) H-bonds. The

403

transition state TS4A converts intermediate R4A into intermediate I4A ( Ea =21.0 kcal/mol).

404

In the intermediate I4A, there is a strong bond formation between ruthenium and N1A

405

(Ru―N1A = 2.14 Å; ρ = 0.086 a. u.), which is also confirmed from electron density value.

406

We have also observed two strong H-bonds (N(imidazole)…..H1NH2A = 2.17 Å; ρ = 0.018 a.

407

u., H2’OH1’…..NH2A = 2.03 Å; ρ = 0.024 a.u.) moderately strong, H2OH1 …..N1A(3.20 Å),

408

H2O’…..H1NH2A

409

N(imidazole)…..H2NH1A (3.83 Å), H1’OH2’…..NH2A (3.48 Å) and H2O’…..H2NH1A(3.63 Å)

410

in the intermediate I4A. Although water ligand is completely dissociated from NAMI-A

411

(Ru―OH2 =4.18 Å) in the intermediate I4A however, it is still remained attached with

412

adenine two weak H- bonds (H2OH1

413


414

In pathway IIA, the intermediate R5A exhibits a weak coordination between Ru3+ and N3A

415

(Ru―N3A = 3.96 Å) (Scheme 2 and Table S6). The existence of two strong H-bonds

416

(H1OH2…..O(DMSO)= 2.03 Å; ρ=0.022 a.u., H2OH1…..N3A =1.63 Å; ρ=0.030 a.u.), two

417

moderate H2O …..HNA(3.37 Å), H1OH2 …..N3A (3.19 Å ) and one weak H2OH1…..O(DMSO)

418

(3.59 Å) in the intermediate R5A contribute to the stability of the intermediate R5A. The

419

intermediate R5A undergoes substitution reaction to form the intermediate I5A through

420

transition state TS5A ( Ea =21.5 kcal/mol). Similar trend of interchange dissociative

421

mechanism is observed in the transition state TS5A where simultaneous Ru―OH2 bond

422

cleavage (2.44Å) and Ru―N3A (2.67Å) bond formation proceeds to the intermediate I5A.

423

Here,

424

H2O…..HNA=2.15; ρ=0.017a.u.), three moderate (H2OH1…..O(DMSO)=2.94Å, H2OH1

425

…..

426

H2OH1…..NHA =3.55 Å and H1OH2…..NHA = 3.25 Å) H-bonds attribute towards the

comprises

two

H1OH2…..N1A

the

(2.82

Å)

(2.73Å)

presence

of

N3A = 2.99 Å, H2’OH1’

H1OH2…..O(DMSO)

strong,

and

and

two …..

three

weak

…..

weak

(1.96Å;

(H2OH1

H-bonds,

…..

N1A

ρ=0.026a.u.,

(3.53

H1OH2…..N1A

Å),

(4.07Å),

N1A = 3.20 Å and H1OH2…..N1A = 4.07 Å).

strong

(H1OH2…..O(DMSO)=

2.03Å;

ρ=0.023a.u.,

N3A = 3.12 Å) and three weak (H1OH2…..N3A =3.62 Å,


Page 19 of 37 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


427

stability of transition states TS5A. The displacement of water ligand from the ruthenium

428

centre by N3A and coordination of N3A with ruthenium (Ru―N3A = 2.09 Å; ρ= 0.095 a.u)

429

result into pseudo-octahedral intermediate, I5A. Here, N3A still remains associated with

430

water ligand through both the hydrogen atoms with weak H-bonds, H2OH1 …..N3A = 3.28 Å,

431

H1OH2…..N3A = 3.76 Å.

432


433

In pathway IIIA, a strong association of Ru―OH2 (2.13 Å; ρ= 0.073 a.u) and a weak

434

Ru―N7A (3.92 Å) bond is seen in the intermediate R6A (Scheme 2). Intermediate R6A

435

possesses two strong H-bonds, H2’OH1’…..O(DMSO)

436

H2’OH1’…..O(DMSO)= 1.61Å; ρ= 0.063 a.u.). In addition to this another hydrogen of water

437

ligand is weakly interacted with N7A (H1OH2…..N7A = 3.14Å) while oxygen of water is

438

moderately interacted with the proton of NH2-A, (H2O …..H1NH2A = 2.45Å). We have also

439

seen that both hydrogen of water ligand gets interacted with nitrogen of of NH2-A,

440

(H2OH1…..NH2A = 3.09 Å, H1OH2…..NH2 A = 3.75 Å). The strong water―DMSO

441

interactions make slow displacement of water ligand from ruthenium coordination centre in

442

the intermediate R6A. Intermediate R6A converts into intermediate I6A through transition

443

state TS6A ( Ea = 20.7 kcal/mol). Transition state TS6A involves the cleavage of Ru―OH2

444

bond and the formation of Ru―N7A bond, which is clearly observed through the change in

445

the bond distances from 3.92 Å in R6A to 2.49 Å in TS6A while as Ru―H2O distance

446

increases from 2.13 Å to 2.55 Å. Accordingly, transition state TS6A explains the movement

447

of adenine towards coordination centre of NAMI-A, while water is moving away from

448

ruthenium centre.

449

(H1OH2…..O(DMSO)= 3.80 Å, H2OH1…..O(DMSO) = 3.23 Å) and moderately strong H-

450

bond between imidazole ligand and adenine (N(imidazole)…..H1NH2A = 2.58 Å ) in the

451

transition state TS6A confirms the movement of adenine towards ruthenium coordination

452

centre through the simultaneous displacement of water ligand. Intermediate I6A obtained

453

through transition state TS6A is stabilized by two strong (H2O’…..H1NH2A= 2.04 Å,

454

H2OH1…..N7A = 2.50 Å), two moderate (H2OH1…..N7A = 3.32 Å, H2’OH1’…..NH2A= 3.17

455

Å) and three weak (N(imidazole)…..H2NH1A= 3.84 Å, H2O’…..H2NH2A = 3.65 Å,

456

H1OH2…..NH2A= 3.65 Å).

(1.91 Å; ρ= 0.028 a.u.) and

Weak H-bonds between water and DMSO ligands of NAMI-A

457 458 19 ACS Paragon Plus Environment


Page 20 of 37

459


460

From the BSSE corrected interaction energy ( E ) it is found that higher activation energy is

461

required for intermediate R4A (-14.9 kcal/mol) to convert into intermediate I4A than R5A (-

462

16.3 kcal/mol) and R6A (-16.9 kcal/mol) into their respective intermediates I5A and I6A.

463

Interaction energy of intermediates R4A, I5A and I6A are consistent with the no. H-bonds

464

present in the intermediates, as described above. The calculated E a for the interaction

465

reaction of NAMI-A with adenine is found approximately identical N7 (20.7 kcal/mol)  N1

466

(21.0 kcal/mol)  N3 (21.5 kcal/mol) which created the confusion about the preference of the

467

reactivity of these nitrogen centres towards NAMI-A (Figure 5). To understand the relevance

468

of order of reactivity found in the experimental results we studied the H-bonds between water

469

and DMSO ligands in NAMI-A. Surprisingly, we found that number and strength of H-bond

470

in these interactions are equally contributing towards the stability of the transitions states and

471

hence the activation energy barrier is almost similar. While careful evaluation of H-bond

472

distances in these interactions we found that water and DMSO ligands H-bond distances play

473

vital role. Therefore the stronger OH2-DMSO bonds make displacement of water ligand slow

474

while as weaker OH2-DMSO bonds attribute towards the faster displacement of water ligand.

475

On the basis of these observations the order of reactivity of these nitrogen centres should be

476

N3 (OH2-DMSO =2.03 and 2.94 Å)  N1 (OH2-DMSO =1.96 and 3.17Å) < N7 (OH2-DMSO

477

= 3.80 and 3.23 Å) and this is in agreement with the experimental results.39

478


Page 21 of 37 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


479 480


481

diaqua NAMI-A with N1A, N3A and N7A. Activation barrier (kcal/mol) are shown in

482

the squares along the reaction path.

483

3.1.3. Molecular orbital (MO) diagram analysis

484

In the interaction mechanism of anticancer drug-DNA adduct, DNA molecule acts as an

485

electron donor and the drug molecule is an electron acceptor.40 In general, a donor-acceptor

486

interaction is observed between the highest occupied molecular orbital (HOMO) of DNA and

487

lowest unoccupied molecular orbital (LUMO) of drug molecule. In the molecular orbital

488

study, we found that Ru dxy (LUMO) and N7 px (HOMO) orbitals participate in donor-

489

acceptor interactions as accepting and donating orbitals respectively. It is also observed that

490

lone-pair orbital px of N7 mixes with the nearing p-orbitals of the purine ring and forms a

491

fairly delocalized orbital in purine bases and hence lowers the energy of the HOMO. In

492

purine bases, HOMO energy is found to be -6.47 eV and -6.78 eV for guanine and adenine

493

respectively. The iso-surface plots reveal that N7 px orbital of adenine and guanine act as

494

electron donors which readily coordinates with dxy orbital of Ru fragment. As a result, a

495

stronger donor-acceptor interaction with good orbital overlap is observed between

496

guanine/adenine and ruthenium of NAMI-A (Figure 6).



Page 22 of 37

497 498

Figure 6 MO diagram of interaction of diaqua NAMI-A and purine bases

499

3.2 Interaction of NAMI-A-DNA adduct

500

In this work, the effects of NAMI-A on the interactions between two strands of guanine-

501

cytosine (GC) and adenine-thymine (AT) dinucleotides have been investigated. When we

502

have calculated the binding energies for NAMI-A-DNA adducts, it is observed that

503

monoaqua GCmono-NAMI-A (32.2 kcal/mol) and ATmono-NAMI-A

504

adducts have higher positive binding energy value than GCdi-NAMI-A (-13.0 kcal/mol) and

505

ATdi-NAMI-A (3.16 kcal/mol) respectively. These results are an indicative of weaker

506

binding between monoaqua NAMI-A and AT/GC dinucleotides than diaqua NAMI-A and

507

AT/GC dinucleotides. AIM Analysis and Becke surface analysis were performed in order to

508

understand the effect of electron density and pi-stacking energy on the energy differences in

509

NAMI-A-DNA nucleotides.41-44

510

3.2.1. AIM analysis

511

In guanine-cytosine (GC) and adenine-thymine (AT) dinulceotides, in addition to the normal

512

Watson–Crick pairing like GC and AT, there can be two another stacking interactions which

513

are intra-strand(S) and inter-strand (IS). In free GC dinucleotide, π-stacking interactions have

514

been estimated at GGS= -1.2, CCS= -2.3 and GCIS= - 4.3 kcal/mol (Table 2). In comparison

515

to free GC dinucleotide, in GCmono-NAMI-A adduct, π-stacking value of GGS is reduced to

(29.6 kcal/mol,


Page 23 of 37 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


516

-2.0 kcal/mol while as CCS and GCIS π-stacking values are increased to -1.6 kcal/mol and -

517

2.5 kcal/mol respectively. In bifunctional adduct, GCdi-NAMI-A the effect of ruthenation is

518

more distinct as there is only disruption of intra-strand π-stacking between guanine residues,

519

which is deviated by ~2.3 kcal/mol from the original value. Similarly, in free AT

520

dinucleotide, the π-stacking interactions are observed at AAS= -2.2, TTS= -1.6 and ATIS= -3.6

521

kcal/mol. However, in both ATmomo-NAMI-A and ATdi-NAMI-A adduct, all π-stacking

522

interactions of AAS, TTS, ATIS are increased as compared to free AT dinucleotides (Table 2).

523

This indicates that upon NAMI-A interaction distortion occurs in residues of GC and AT

524

dinucleotides and the planarity of base pairs gets deviated which results into change in

525

binding energy. The loss of inter base hydrogen bonds in DNA nucleotides and the formation

526

of new hydrogen bonds between NAMI-A and adenine/guanine residues might be responsible

527

for these distortions.

528 529

Table 2. Electron density  (a.u.) and π-stacking energy E (kcal/mol) of free and NAMIA interacted GC and AT nucleotides



E (kcal/mol)

DNA

Hydrogen

Nucleotides

Bond

(5/)-(3/)

(3/)-(5/)

O6…..H4

0.037

0.037

H2…..O2

0.027

0.28

H1…..N3

0.033

0.033

O6…..H4

0.029

0.037

H2…..O2

0.027

0.027

H1…..N3

0.033

0.032

O6…..H4

0.031

0.034

H2…..O2

0.032

0.033

H1…..N3

0.037

0.035

H6….O4

0.030

0.028

N1…..H3

0.038

0.043

ATmono-

H6….O4

0.030

0.019

NAMI-A

N1…..H3

0.037

0.044

ATdi-

H6….O4

0.040

0.019

NAMI-A

N1…..H3

0.025

0.040

GC

GCmonoNAMI-A

GCdiNAMI-A AT

GG(S)/AA(S)

CC(S)/TT(S)

GC(IS)/AT(IS)

-1.2

-2.3

-4.3

-2.0

-1.6

-2.5

-3.5

-3.0

-5.0

-2.2

-1.6

-3.6

-2.7

-1.7

-6.4

-2.8

-1.8

-4.8

530



Page 24 of 37

531

Similar to platination, ruthenation is also known to affect Watson–Crick pairing GC and AT.

532

It is seen that ruthenation weakens O6G…..H4C bond but H1G···N3C and H2G···O2C bonds

533

remain unchanged in GCmono-NAMI-A adduct as compared to free GC nucleotide (Figure

534

7). In bifunctional adduct GCdi-NAMI-A, ruthenation weakens the O6G…..H4C whereas

535

H1G···N3C and H2G···O2C bonds gets strengthened. As a result, in GCdi-NAMI-A adduct,

536

both the GC base pairs get affected by NAMI-A interaction, whereas in the GCmono-

537

NAMI-A only GC base pairs get deviated from their planarity. Similarly, hydrogen bond

538

disruption between adenine and thymine bases are observed in ATmono-NAMI-A and

539

ATdi-NAMI-A adducts (Table 2). Thus, we could quantify the disruption of GC/AT base

540

pair in DNA dinucleotide by topological analysis and which results into change in binding

541

energy between mono and bifunctional adducts.

542

GC dinucleotide

543 544 545


Page 25 of 37 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

546


GCmono-NAMI-A

547

548 549

GCdi-NAMI-A

550



Page 26 of 37

551

Figure 7. Optimized structures of GC dinucleotide and GCmono-NAMI-A and GCdi-

552

NAMI-A adducts calculated at M06/(LANL2DZ+6-31G(d,p) level. Electron density (in a.u.)

553

values for (G5/)-(C3/) are shown.

554 555

3.2.2. Becke surface analysis

556

The Becke surface analyses show that the intermolecular interaction between the GC and AT

557

base pairs. Here, hydrogen bonds between GC and AT base pairs are represented by six

558

electron dots and four electron dots in electron density regions respectively (Figure 8a and

559

8b). It is observed that intensity of electron density at the red zone of GC dinucleotide

560

decreases

561

4(O6…..H4)>5(H1…N3)>6(H2…O2); which also represents the strength of corresponding

562

hydrogen bonds. On the other hand, in AT dinucleotide, the value of electron density based

563

on the red zones indicates the decrease in the hydrogen bond strengths in order of

564

2(N1…..H3)>1(H6….O4) and 4(N1…..H3)>3(H6….O4).

565

(a)

in

following

order

1(O6…..H4)>2(H1….N3)>3(H2…..O2)

and

566

1= 0.076 a.u. 4= 0.075 a.u. 2= 0.065 a.u. 5= 0.063 a.u. 3= 0.052 a.u. 6= 0.055 a.u.

567 568 569 570 571 572 573 574 575 576 577

GC

578 26 ACS Paragon Plus Environment

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579


(b)

580

1= 0.060 a.u. 3= 0.055 a.u. 2= 0.075 a.u. 4= 0.084 a.u.

581 582 583 584 585 586 587 588

AT

589

Figure 8. Becke surface of (a) GC and (b) AT dinucleotide

590

After the interaction of monoaqua NAMI-A with GC and AT, the electron density at the red

591

point 1 decreases considerably from 0.076 a.u. to 0.054 a.u. and 0.060 a.u.to 0.048 a.u.

592

(Figure 8-9). In case of GCmono-NAMI-A adduct, the electron density at the red point 2

593

increases from 0.065 a.u. to 0.076 a.u. (Figure 8-9a) whereas, in ATmono-NAMI-A adduct

594

it is slightly decreased from 0.075 a.u. to 0.072 a.u. (Figure 8-9b). On the other hand, in

595

GCmono-NAMI-A adducts the electron density remains almost unchanged at the other three

596

red zones (4, 5 and 6) of the base pair in which the guanine molecule is not directly bound to

597

the ruthenium centre of NAMI-A (Figure 9a).

598 599 600 601 602 603 604

(a)



605

Page 28 of 37

1= 0.054 a.u. 4= 0.075 a.u. 2= 0.076 a.u. 5= 0.064 a.u. 3= 0.051 a.u. 6= 0.054 a.u.

606 607 608 609 610 611 612 613 614 615 616

GCmono-NAMI-A

617 618 619 620 621 622 623 624 625 626 627 628


Page 29 of 37 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

629


(b)

630

1= 0.048 a.u. 3= 0.035 a.u. 2= 0.072 a.u. 4= 0.089 a.u.

631 632 633 634 635 636 637 638 639 640 641

ATmono-NAMI-A Figure 9. Becke surface of (a) GCmono-NAMI-A and (b) ATmono-NAMI-A adduct

642

In both GCdi-NAMI-A and ATdi-NAMI-A adducts, the extensive change in electron

643

density at all the red zones resulted into the disruption of the base pairs as compared to the

644

isolated base pairs (Figure 10). These results states that GCdi-NAMI-A and ATdi-NAMI-A

645

could be more active drug candidate than GCmono-NAMI-A and ATmono-NAMI-A

646

respectively.

647 648 649 650 651 652 653



654

Page 30 of 37

(a) 1= 0.062 a.u. 4= 0.068 a.u. 2= 0.074 a.u. 5= 0.068 a.u. 3= 0.064 a.u. 6= 0.067 a.u.

655 656 657 658 659 660 661 662 663 664 665

GCdi-NAMI-A (b)

666 667

1= 0.082 a.u. 3= 0.036 a.u. 2= 0.048 a.u. 4= 0.070 a.u.

668 669 670 671 672 673 674 675 676 677

ATdi-NAMI-A Figure 10. Becke surface of (a) GCdi-NAMI-A and (b) ATdi-NAMI-A adduct


Page 31 of 37 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


678

4.Conclusion

679

In this work we have investigated the relation between hydrogen bonding and preferred

680

binding sites of guanine and adenine for the interaction of NAMI-A using density functional

681

theory method. Our computational model shows that the interaction reactions follow

682

interchange dissociative mechanism except in diaquated NAMI-A-guanine interaction at N3

683

site proceeds through dissociative mechanism. The N7G is the most favourable position in

684

interaction reaction of guanine with monoaqua and diaqua NAMI-A because transition states

685

involved here are stabilized by more H-bonds than N3G. On the other hand, interaction

686

reactions of adenine with monoaqua and diaqua NAMI-A favours N3A and N7A sites

687

respectively. In overall study it is found that H-bonding plays a significant role in the

688

interaction reaction of NAMI-A with purine bases. These ruthenium-nitrogen bond formation

689

reactions in ruthenated purine bases is validated by MO study. The model study on

690

interaction of N7A with NAMI-A at 310.15 K suggested that computational results obtained

691

at 298.15 K are valid under physiological conditions too. The interaction of NAMI-A with

692

double stranded DNA dinucleotide leads to deviation of the planarity of base pairs, GC and

693

AT. AIM analysis is used in order to monitor the effect of ruthenation on hydrogen bonding

694

and π-stacking in DNA nucleotide. AIM analysis displays hydrogen bonding pattern in

695

GC/AT base pair as well as π-stacking interactions between GG/AA, CC/TT and GC/AT pair

696

are disrupted on ruthenation. In AIM and Becke surface analysis, interaction reactions of

697

DNA with NAMI-A show a significant disruption of DNA strands in diaqua adducts over

698

monoaqua adducts. This suggests that diaqua NAMI-A could be better anticancer properties

699

than monoaqua NAMI-A. This study also endorses metal-based anticancer drugs with more

700

H-bond formation opportunities could have more reactivity towards nucleotide bases and

701

hence could serve as better anticancer agents. In a way, this study could also be useful in

702

understanding the effect of hydrogen bonding towards the reactivity of metal-based drugs

703

with DNA nucleotide; which can be further extended to understand many biochemical events

704

in life sciences, biomedical and chemical science.

705 706 707 708 709 31 ACS Paragon Plus Environment


Page 32 of 37

710

Supporting information

711

Cartesian coordinates of all the relevant structures, Tables S1-S9, Optimized Figures S1 and

712

S2 is free of cost on https://pubs.acs.org/

713 714 715 716 717 718 719 720 721 722 723 724 725 726

AUTHOR INFORMATION Corresponding Author *E-mail:[email protected] *[email protected]

727

S.P. acknowledges the J.C. Bose Fellowship grant of DST. V.A. thanks UGC-New Delhi for

728

the research grant. D.D and M.S.K thank Indian Institute Technology Bombay for IF

729

(Institute Fellowship). GB thanks to CSIR fellowship. We also thank I.I.T. Bombay computer

730

centre facility

Notes The authors declare no competing financial interest. Present Address: § Indian Institute of Science Education and Research Kolkata, Mohanpur, 741246, West Bengal, India ACKNOWLEDGEMENTS

731 732

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