ARTICLE pubs.acs.org/JPCA
Mechanistic Study of the Deamination Reaction of Guanine: A Computational Study Kabir M. Uddin,† Mansour H. Almatarneh,† Dawn M. Shaw,‡ and Raymond A. Poirier*,† †
Department of Chemistry and ‡The Atlantic Computational Excellence Network, Memorial University, St. John’s, Newfoundland, Canada A1B 3X7
bS Supporting Information ABSTRACT: The mechanism for the deamination of guanine with H2O, OH-, H2O/OH- and for GuaHþ with H2O has been investigated using ab initio calculations. Optimized geometries of the reactants, transition states, intermediates, and products were determined at RHF/6-31G(d), MP2/6-31G(d), B3LYP/6-31G(d), and B3LYP/6-31þG(d) levels of theory. Energies were also determined at G3MP2, G3MP2B3, G4MP2, and CBS-QB3 levels of theory. Intrinsic reaction coordinate (IRC) calculations were performed to characterize the transition states on the potential energy surface. Thermodynamic properties (ΔE, ΔH, and ΔG), activation energies, enthalpies, and Gibbs free energies of activation were also calculated for each reaction investigated. All pathways yield an initial tetrahedral intermediate and an intermediate in the last step that dissociates to products via a 1,3-proton shift. At the G3MP2 level of theory, deamination with OH- was found to have an activation energy barrier of 155 kJ mol-1 compared to 187 kJ mol-1 for the reaction with H2O and 243 kJ mol-1 for GuaHþ with H2O. The lowest overall activation energy, 144 kJ mol-1 at the G3MP2 level, was obtained for the deamination of guanine with H2O/OH-. Due to a lack of experimental results for guanine deamination, a comparison is made with those of cytosine, whose deamination reaction parallels that of guanine.
1. INTRODUCTION Guanine (Gua), is one of the purine bases that occurs naturally in both DNA and RNA. It is chemically linked to the sugar moiety via a covalent bond on the N9 site of the purine ring and interacts with other nucleic acid bases via hydrogen bonds, most frequently with cytosine.1 The deamination of guanine occurs in vitro under physiological conditions at rates much lower than for cytosine and also occurs on the order of 10-4 times the rate of loss of these bases from DNA. Under physiological conditions, nucleic acid base tautomers yield observed frequencies of spontaneous substitution mutations of 10-8-10-10 (In Vivo) and 10-5-10-6 (in vitro).2,3 The formation of xanthine in DNA arising from the deamination of guanine is of biological importance. Xanthine is unable to form stable pairs with either cytosine or thymine and thus may halt the production of DNA that employs templates containing this base. Chemicals that oxidize DNA are of interest due to their antibiotic, antitumor, carcinogenic, and mutagenic properties.4 Also of interest are nitrosating reagents, which represent an important class of DNA-damaging agents.5 Nitrous acid causes deamination of guanine residues in DNA6-8 and formation of cross-linked DNA strands.9-12 Furthermore, bisulfide-induced deamination has been well-studied under physiological conditions and involves several pathways, namely acid-catalyzed hydrolysis,13 thermal hydrolysis,14 and base-15 and acidcatalyzed16 deamination. r 2011 American Chemical Society
Yao et al.17 employed B3LYP/6-31G(d) within a two-layer ONIOM model to study the hydrolytic deamination of guanine to xanthine by guanine deaminase, a Zn metalloenzyme that plays a critical role in the catalytic breakdown of guanine.18 They also studied19 the hydrolysis of cytosine to uracil by yeast cytosine deaminase. Zhang et al.20 studied the hydrolytic deamination of adenine at the B3LYP/6-31G(d,p) level of theory and found two different mechanisms. Sponer et al.21 studied deamination of cytosine with OH- using the PCM model to account for solvation effects and also studied metal-mediated deamination of 1-methylcytosine and 1,5-dimethylcytosine with a PtII complex. Their work included both experimental and computational results, where the computational work employed DFT. However, their reported activation energy [213 kJ mol-1 at B3LYP/6-31G(d)] was not very close to the experimentally accepted value (117 ( 4 kJ mol-1).22,23 Rayat et al. studied the nitrosative deamination reactions of both guanine24 and cytosine25 and found several possible pathways, from which they proposed that the reactions proceed via a pyrimidine ringopened intermediate. For both guanine and cytosine, the intermediates were formed by dediazoniation and deprotonation of the guaninediazonium ion. Glaser et al.26 studied nitrosative Received: December 20, 2010 Revised: February 2, 2011 Published: February 22, 2011 2065
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Table 1. Activation Energies, Enthalpies of Activation, and Gibbs Free Energies of Activation for the Deamination of Guanine with H2O (in kJ mol-1) at 298.15 K (Pathway A)a HF/ MP2/ B3LYP/ B3LYP/ CBS6-31G(d) 6-31G(d) 6-31G(d) 6-31þG(d) G3MP2 G4MP2 QB3 ΔEa,TS1A ΔHqTS1A ΔGqTS1A ΔEa,TS2A ΔHqTS2A ΔGqTS2A ΔEa,TS3A ΔHqTS3A ΔGqTS3A
157 136 146 245 237 245 191 176 177
106 83 90 201 189 198 139 124 123
90 69 76 197 186 192 131 116 116
95 73 81 227 219 225 132 118 119
85 (85)b 82 89 187 (187)b 185 191 135 (135)b 134 134
86 83 90 187 185 191 136 135 136
82 78 86 189 187 193 131 131 131
a
Barriers were calculated from the Gua 3 3 3 H2O complex as defined in Figures 2 and 4. b The values in parentheses are for the G3MP2B3 level of theory.
guanine deamination in the presence of cytosine and have found that the mechanisms reported depend highly on the environment in which the studies were conducted. Recently, Matsubara et al.27 studied both the uncatalyzed and cytidine deaminase catalyzed hydrolytic deamination of cytosine, adding a single H2O for the uncatalyzed mechanism. They found that the catalytic action of cytidine deaminase is effectively enhanced by the participation of the extra water molecule. Their reported27 activation energy barrier with one water molecule is 237 kJ mol-1 at the B3LYP/631G(d,p) level. No high-level computational studies have been reported for the deamination reaction mechanism of guanine, and no experimental work has thus far been conducted. This paper represents a detailed computational study of the deamination reaction of guanine with H2O, OH-, H2O/OH-, and protonated guanine (GuaHþ) with H2O. To ensure the reliability of our results, both wave function and DFT calculations were performed.
2. COMPUTATIONAL METHODS All the electronic structure calculations were performed with the program Gaussian 09.28 The geometries of all reactants, transition states, intermediates, and products were fully optimized at the RHF, MP2, and B3LYP levels of theory using the 6-31G(d) basis set and at B3LYP/6-31þG(d). From our previous work,29 it was found that the activation energies and the heats of reaction calculated using several different Gaussian-n theories all agreed to within 10 kJ mol-1, which is within the reported error of the Gaussian-n theories in the literature. Energies have also been calculated at the G3MP2,30 G3MP2B3,31 G4MP2,32,33 and CBSQB3 levels.34 On the basis of these results, we chose single point energy calculations employing the G3MP2 level of theory, which is the least computationally expensive method for providing reliable energetics. Where B3LYP failed to locate a transition state structure along one of the reaction pathways, two long-range corrected hybrid density functionals, Coulomb-attenuating B3LYP (CAMB3LYP)35 and M05-2X,36 were also employed. For all the mechanisms discussed in this study, the transition states were analyzed using the intrinsic reaction coordinate (IRC) method. Structures obtained from IRC were optimized in order to identify the reactant and product to which each transition state is connected. Frequencies were calculated for all structures to ensure the absence of imaginary frequencies in the minima and for the presence of only one imaginary frequency in the transition states.
Figure 1. Deamination reactions of guanine with H2O, protonated guanine with H2O with two products, guanine with OH- with two possible products, and guanine with H2O/OH- with three possible products.
3. RESULTS AND DISCUSSION The results for the deamination reaction of guanine with H2O, OH-, H2O/OH-, and GuaHþ with H2O at the different levels of theory are given in Tables 1-10. Deamination reactions of guanine studied along with possible products are shown in Figure 1. The optimized structures and the relative energies of reactants, intermediates, transition states, and products for all pathways are shown in Figures 2-17. 3.1. Potential Energy Surfaces for the Deamination Reaction of Guanine with H2O. The results for the deamination of
guanine with H2O can follow one of two possible pathways, designated as pathways A and B. The structures of reactants, intermediates, transition states, and products involved in both mechanisms are shown in Scheme 1. The optimized structures of reactants, intermediates, transition states, and products for pathways A and B are shown in 2066
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Figure 2. Optimized structures along pathway A for the deamination of guanine with H2O.
Figures 2 and 3. The relative energies of reactants, intermediates, transition states, and products are shown in Figures 4 and 5. The activation energies, Gibbs free energies, and enthalpies of activation calculated at RHF/6-31G(d), MP2/6-31G(d), B3LYP/6-31G(d), and B3LYP/6-31þG(d) levels of theory and Gaussian-n theories for pathways A and B are given in Tables 1 and 2, respectively. Pathway A is a three-step reaction mechanism. The first step is a tautomerization reaction of the Gua/H2O complex with activation energies of 85, 85, 86, and 82 kJ mol-1 at G3MP2, G3MP2B3, G4MP2, and CBS-QB3, respectively. The second step of pathway A is rate-determining. In this step, nucleophilic attack by the water molecule on the C2 site and simultaneous proton transfer from H2O to the sp2 nitrogen (N10) of guanine results in a tetrahedral intermediate (I2A). The activation energies (ΔEa,TS2A) at the G3MP2, G4MP2, G3MP2B3 and CBSQB3 levels of theory are 187, 187, 187, and 189 kJ mol-1, respectively. Finally, the Xan 3 3 3 NH3 complex (PA) is formed via TS3A, which involves an intramolecular 1,3-proton transfer of the hydroxyl hydrogen to the amino group. The activation energies (ΔEa,TS3A) at G3MP2, G4MP2, G3MP2B3, and CBS-QB3 are 135, 136, 135, and 131 kJ mol-1, respectively. The B3LYP/631G(d) and B3LYP/6-31þG(d) results differ from Gaussian-n theories by no more than 5 kJ mol-1. In pathway B, the first step involves formation of intermediate I1B via TS1B, where nucleophilic attack by the oxygen of the water molecule on the C2 site and simultaneous proton transfer from that same water molecule to the N10 site of the amino group yields the hydroxyl-oxo tautomer of xanthine and ammonia, I1B. The activation energies (ΔEa,TS1B) of the rate-determining step at G3MP2, G3MP2B3, and G4MP2 are 265, 265, and 263 kJ mol-1, respectively. The final step is an internal proton transfer (1,3-shift) of the hydroxyl hydrogen to the N3 site of the tautomer to form the Xan 3 3 3 NH3 complex (PB). This has been
confirmed by IRC analysis. The activation energies (ΔEa,TS2B) at G3MP2, G3MP2B3, and G4MP2 are 152, 152, and 152 kJ mol1 , respectively. The activation energies for the rate-determining step of guanine for pathways A and B are 187 and 265 kJ mol-1, respectively, at the G3MP2 level of theory. These barriers are similar to the G3MP2 results of cytosine,37 which are 221 and 260 kJ mol-1, respectively. 3.2. Potential Energy Surfaces for the Deamination Reaction of Protonated Guanine (GuaHþ) with H2O. In this study, protonated guanine forms three complexes with H2O, R1C and R1D/R1E, with a proton at the N3 and N10 sites, respectively. Previous studies on the proton affinities for adenine38,39 and guanine40 indicate that gas-phase protonation depends on the proton affinities (PA) of the basic centers, N1, N3, N7, N9, and the amino group (N10). The proton affinity (PA) and basicity (GB) are defined as the change in the enthalpy and Gibbs free energy, respectively. The calculated proton affinity (PA) and basicity (GB) of neutral guanine at the N3, N7, and N10 sites (Figure 6) are given in Table 3. The PA of the N3, N7, and N10 sites of guanine computed at G3MP2 are 887, 954, and 798 kJ mol-1, respectively, while the experimental value41 is 950 ( 12 kJ mol-1. Similarly, the GB value of the N3, N7, and N10 sites of guanine at G3MP2 is 856, 923, and 768 kJ mol-1, while the experimental value41 is 916 ( 12 kJ mol-1. The G3MP2 proton affinities are found to be close to those of the N3 and N7 site obtained using B3LYP/6-31þG(d) (850 and 920 kJ mol-1, respectively) and differ by no more than 6 kJ mol-1. The computed PA values of the N7 site at G3MP2 and G4MP2 are in good agreement with the experimental41 value, differing by only 4 kJ mol-1. Previous calculations at B3LYP/6-31þG(d,p)42 of the PA of cytosine (N3 site) and guanine (N3 site) gave values of 956 and 887 kJ mol-1, respectively. 2067
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Scheme 1. Reaction Mechanism for the Deamination of Guanine with H2O (Pathways A and B)
The three GuaHþ/H2O complexes lead to three possible pathways, designated as C, D, and E. The optimized structures of reactants, intermediates, transition states, and products for pathways C, D, and E are shown in Figures 7 and 8. The relative energies of reactants, intermediates, transition states, and products are shown in Figures 9 and 10. Activation energies, Gibbs free energies, and enthalpies of activation are given in Tables 4-6. In pathway C, protonated guanine [GuaHþ(N3)] forms a GuaHþ 3 3 3 H2O complex (R1C). Pathways D and E involve two different GuaHþ(N10) 3 3 3 H2O complexes. In pathways C and D, nucleophilic attack by the water molecule on the C2 site of GuaHþ (Figure 7) results in the formation of the intermediate cation (I1C/D). This was confirmed by intrinsic reaction coordinate
(IRC) analysis of the two transition states. The activation energies of the rate-determining step, (ΔEa,TS1C) and (ΔEa,TS1D), are 274 and 258 kJ mol-1, respectively at G3MP2. The G3MP2 values are found to be close to those obtained using B3LYP/631G(d) and differ by no more than 1 kJ mol-1. Intermediate I1C/D is converted to intermediate I2C/D (a complex of XanHþ C/D 3 3 3 NH3) via transition state TS2 -1. The activation energy for this step (ΔEa,TS2C/D) is -2 kJ mol at G3MP2. Comparison of the results of this step with those of B3LYP is not possible due to convergence failure in the transition state optimization with this hybrid functional. A possible reason for this failure is the significant van der Waals contribution from the interaction of the NH3 with the guanine complex at the C2 site. The inability of 2068
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Figure 3. Optimized structures along pathway B for the deamination of guanine with H2O.
Figure 4. Pathway A for the deamination of guanine with H2O. Relative energies (in kJ mol-1) are at the G3MP2 level of theory.
Figure 5. Pathway B for the deamination of guanine with H2O. Relative energies (in kJ mol-1) are at the G3MP2 level of theory.
Table 2. Activation Energies, Enthalpies of Activation, and Gibbs Free Energies of Activation for the Deamination of Guanine with H2O (in kJ mol-1) at 298.15 K (Pathway B)a HF/
MP2/
B3LYP/
B3LYP/
6-31G(d) 6-31G(d) 6-31G(d) 6-31þG(d)
G3MP2
G4MP2
ΔEa,TS1B
343
260
256
254
265 (265)
ΔHqTS1B
336
250
246
247
259
258
ΔGqTS1B ΔEa,TS2B
351 214
265 162
261 155
259 161
274 152
272 152
ΔHqTS2B
199
147
141
146
152 (152) b
152
ΔGqTS2B
198
146
140
145
151
152
b
263
a
Barriers were calculated from the Gua 3 3 3 H2O complex as defined in Figures 3 and 5. b The values in parentheses are for the G3MP2B3 level of theory.
DFT functionals to model long-range phenomena like van der Waals interactions is well-known,43-48 and as a result, some research groups have added long-range corrections to some of the functionals specifically to correct this deficiency. CAMB3LYP35 and M05-2X36 were employed to determine if the long-range interactions were significant enough to prevent the
Figure 6. Gas-phase protonation sites of guanine [GuaHþ(N10) and GuaHþ(N3)].
convergence of the search for this transition state. The resulting optimizations do in fact converge to yield the transition state 2069
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(TS2C/D). The final step involves an internal proton transfer from the hydroxyl group to ammonia, giving a more stable Xan 3 3 3 NH4þ complex (PC/D). Table 3. Gas-Phase Proton Affinities (PA) and Basicities (GB) of Guaninea,c (in kJ mol-1) at 298.15 K PA (GuaHþ) level/basis set
N3
GB (GuaHþ)
N7
N10
N3
N7
N10
HF/6-31G(d)
906
974
784
876
943
753
MP2/6-31G(d)
889
958
816
865
925
786
B3LYP/6-31G(d) B3LYP/6-31þG(d)
907 878
978 951
814 789
879 850
947 920
784 759
G3MP2
887
954
798
856
923
768
G4MP2
888
954
799
859
923
769
exptlb
950 ( 12
916 ( 12
a Proton affinity and basicity as defined in Figure 6. b The proton affinity and the basicity experimental values are taken from ref 41. c The gasphase protonation reaction, A- þ Hþ f AH.
Figure 7. Optimized structures along pathways C and D for the deamination of protonated guanine (GuaHþ) at N3 and N10 sites with H2O.
In pathway E, nucleophilic attack by the water molecule on the C2 site and simultaneous proton transfer from H2O to the sp3 nitrogen (N10) of guanine result in the production of a xanthine tautomer ammonium ion complex (I1E). The activation energy for this rate-determining step (ΔEa,TS1E) at G3MP2 is 243 kJ mol-1. Finally, internal proton transfer from the hydroxyl group to the N3 atom of the tautomer results in the deamination product (PE), a Xan 3 3 3 NH4þ complex. The activation energy (ΔEa,TS2E) at G3MP2 is 106 kJ mol-1. The activation energies for the rate-determining step of guanine for pathways C, D, and E are all high, 274, 258, and 243 kJ mol-1, respectively, at the G3MP2 level of theory. 3.3. Potential Energy Surfaces for the Deamination Reaction of Guanine with OH-. In this study, only one pathway was found for the deamination of guanine with OH-, designated pathway F. The structures of reactants, intermediates, transition states, and products for pathway F are shown in Figure 11. The relative energies are shown in Figure 12. Activation energies, Gibbs free energies, and enthalpies of activation for the reaction of guanine with OH- are given in Table 7. Deprotonation enthalpies [PA(A-)] of the N1 and N10 sites of guanine employing HF/6-31G(d), MP2/6-31G(d), B3LYP/ 6-31G(d), B3LYP/6-31þG(d) levels of theory and Gaussian-n theories are indicated in Table 8. The PA(A-) of the N1 and N10 sites of guanine computed at G3MP2 are 1414 and 1405 kJ mol-1, respectively. These values are close to those computed42 at
Figure 9. Pathways C and D for the deamination of protonated guanine (GuaHþ) at N3 and N10 sites with H2O. Relative energies (in kJ mol-1) are at the G3MP2 level of theory.
Figure 8. Optimized structures along pathway E for the deamination of protonated guanine (GuaHþ) at N10 site with H2O. 2070
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B3LYP/6-31þG(d,p), 1416 and 1412 kJ mol-1, respectively, and differ by less than 7 kJ mol-1. The deprotonation enthalpies for the N1 and N10 sites of guanine (1416 and 1412 kJ mol-1) and the N7 site of cytosine (1482 kJ mol-1) determined42 at the B3LYP/6-31þG(d,p) level of theory differ by less than 66 kJ mol-1 (Figure 13 and 17). Deprotonation at the amino group (N10 site) by the hydroxide ion forms a Gua-(N10H) 3 3 3 H2O complex (R1F). The complex is very stable due to delocalization of the negative charge. The first step of the reaction is a nucleophilic attack by the H2O at the C2 site and a simultaneous hydrogen addition to the imine nitrogen (N10), resulting in the tetrahedral intermediate anion, I1F. The activation energy of the rate-determining step (ΔEa,TS1F) at G3MP2 is 155 kJ mol-1. The G3MP2 value is also found to be close to the B3LYP/6-31þG(d) value (151 kJ mol-1). The activation energy for the deamination of cytosine37 with OH- at the G3MP2 level of theory is slightly
Figure 10. Pathway E for the deamination of protonated guanine (GuaHþ) at the N10 site with H2O. Relative energies (in kJ mol-1) are at the G3MP2 level of theory.
lower (148 kJ mol-1). In the second step, deamination occurs by an intramolecular proton transfer from the hydroxyl group to the amino group (N10 atom) to yield a hydrogen-bonded Xan-(N3) 3 3 3 NH3 (PF) complex. The activation energy (ΔEa,TS2F) at G3MP2 is 98 kJ mol-1. The overall activation energies are 189 and 195 kJ mol-1 at G3MP2 and B3LYP/6-31þG(d) levels of theory, respectively. This complex could easily be protonated to form the final product (Xan 3 3 3 NH3 complex). Previous theoretical studies on 1,3-isomerization49 have shown that the energy barrier can be reduced by as much as 126 kJ mol-1, if the process occurs through a water molecule. The deamination pathway with OH- has a significantly lower activation energy than deamination with H2O and GuaHþ with H2O. 3.4. Potential Energy Surfaces for the Deamination Reaction of Guanine with H2O/OH-. Two pathways, labeled G and H, were studied for the reaction of guanine with H2O/OH-. For these pathways, we have determined a number of possible hydrogen-bonded complexes between guanine, H2O, and OH-. The structures of reactants, intermediates, transition states, and products for pathways G and H are shown in Figures 14 and 15, respectively. The relative energies of reactant, intermediates, transition states, and product for pathways G and H are shown in Figure 16. The activation energies, Gibbs free energies, and enthalpies of activation for pathways G and H are given in Tables 9 and 10, respectively. In pathway G, deprotonation of guanine by OH- occurs easily at the N1 site, forming the Gua-(N1) 3 3 3 H2O 3 3 3 H2O complex (R1G) . This complex is highly stabilized due to the delocalization of the negative charge. In the first rate-determining step, the addition of a water molecule stabilizes the hydroxide ion being formed in the transition state (TS1G), resulting in a lowering of the activation energy. Nucleophilic attack by the water molecule on the C2 site and simultaneous proton transfer from H2O to the exocyclic imine nitrogen of the guanine anion results in the formation of a tetrahedral intermediate (I1G). The activation
Table 4. Activation Energies, Enthalpies of Activation, and Gibbs Free Energies of Activation for the Deamination of GuaHþ(N3) with H2O (in kJ mol-1) at 298.15 K (Pathway C)a HF/6-31G(d)
MP2/6-31G(d)
B3LYP/6-31G(d)
B3LYP/6-31þG(d)
CAM-B3LYP/6-31G(d)
M05-2X
G3MP2
ΔEa,TS1C
343
270
273
279
269
264
274
ΔHqTS1C
330
259
261
266
257
251
270
ΔGqTS1C
341
270
271
276
266
259
280
ΔEa,TS2C
12
7
b
b
1
3
-2
ΔHqTS2C
4
0
b
b
-3
-2
-1
ΔGqTS2C
2
-2
b
b
-3
-2
-2
þ
a
Barriers were calculated from the GuaH (N3) 3 3 3 H2O complex as defined in Figures 7 and 9. b Indicates missing values due to failure to optimize the transition state.
Table 5. Activation Energies, Enthalpies of Activation, and Gibbs Free Energies of Activation for the Deamination of GuaHþ(N10) with H2O (in kJ mol-1) at 298.15 K (Pathway D)a
a
HF/6-31G(d)
MP2/6-31G(d)
B3LYP/6-31G(d)
B3LYP/6-31þG(d)
CAM-B3LYP/6-31G(d)
M05-2X
G3MP2
ΔEa,TS1D
329
272
261
201
229
232
258
ΔHqTS1D
314
258
247
186
215
216
256
ΔGqTS1D
326
268
254
197
217
217
263
ΔEa,TS2D
12
7
b
b
1
3
-2
ΔHqTS2D ΔGqTS2D
4 2
0 -2
b
b
b
b
-3 -3
-2 -2
-1 -2
þ
Barriers were calculated from the GuaH (N10) 3 3 3 H2O complex as defined as Figures 7 and 9. b Indicates missing values due to failure to optimize the transition state. 2071
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Table 6. Activation Energies, Enthalpies of Activation, and Gibbs Free Energies of Activation for the Deamination of GuaHþ(N10) with H2O (in kJ mol-1) at 298.15 K (Pathway E)a HF/6-31G(d)
MP2/6-31G(d)
B3LYP/6-31G(d)
B3LYP/6-31þG(d)
G3MP2
G4MP2
ΔEa,TS1E
284
246
227
235
243 (243)
244
ΔHqTS1E ΔGqTS1E
275 281
237 241
217 219
226 230
256 263
245 245
ΔEa,TS2E
166
122
111
115
106 (106)b
105
TS2E
150
107
96
101
106
105
ΔGqTS2E
148
99
96
100
106
106
ΔH
q
b
Barriers were calculated from the GuaHþ(N10) 3 3 3 H2O complex as defined in Figures 8 and 10. b The values in parentheses are for the G3MP2B3 level of theory. a
Figure 11. Optimized structures along pathway F for the deamination of guanine with OH-.
Table 7. Activation Energies, Enthalpies of Activation, and Gibbs Free Energies of Activation for the Deamination of Guanine with OH- (in kJ mol-1) at 298.15 K (Pathway F)a HF/
MP2/
B3LYP/
B3LYP/
6-31G(d) 6-31G(d) 6-31G(d) 6-31þG(d)
G3MP2
G4MP2
ΔEa,TS1F ΔHqTS1F
207 203
193 188
188 182
151 148
ΔGqTS1F
212
194
187
160
ΔEa,TS2F
137
114
87
84
87 (87)b
89
ΔHqTS2F
124
98
74
72
87
89
ΔGqTS2F
123
96
73
72
87
89
b
155 (155) 153
153 151
159
157
Barriers were calculated from the Gua 3 3 3 OH- complex as defined in Figures 11 and 12. b The values in parentheses are for G3MP2B3 level of theory. a
Figure 12. Pathway F for the deamination of guanine with OH-. Relative energies (in kJ mol-1) are at the G3MP2 level of theory. -1
energy (ΔEa,TS1G) at G3MP2 is 139 kJ mol , in excellent agreement with the B3LYP/6-31þG(d) (136 kJ mol-1) result. The process by which intermediate I1G is converted into the product complex PG is shown in Figures 14 and 16. For pathway G the overall activation energy is 200 kJ mol-1 at the G3MP2 level of theory. Figure 17 illustrates the Gua-(N1H) 3 3 3 H2O 3 3 3 H2O and Cyt-(N7H) 3 3 3 H2O 3 3 3 H2O complexes. The activation energy for the rate-determining step (ΔEa,TS1G) at G3MP2 is 139 kJ
mol-1 for the Gua-(N1H) 3 3 3 H2O 3 3 3 H2O complex and is higher than for the Cyt-(N7H) 3 3 3 H2O 3 3 3 H2O complex (115 kJ mol-1)50 due to a higher degree of delocalization of the negative charge. The reaction of guanine with H2O/OH- has an activation energy for the rate-determining step of 139 kJ mol-1 compared to 155 kJ mol-1 for the same mechanism with OH(without the additional water molecule, pathway F). Pathway H is a two-step mechanism. In the first (rate-determining) step the addition of a water molecule stabilizes the hydroxide ion, forming the transition state (TS1H) and lowering 2072
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the activation energy. Nucleophilic attack by the hydroxide ion on the C2 site results in the formation of a tetrahedral intermediate (I1H). The computed activation energy of the ratedetermining step (ΔEa,TS1H) at G3MP2 is 107 kJ mol-1, in reasonable agreement with the B3LYP/6-31þG(d) value of 114 kJ mol-1. Intermediate I1H is converted to I2H with a slight conformation change in the water molecule. Intermediate I2H is converted to the product via a 1,3-proton shift (transition state TS2H) and is mediated by a single water molecule, as shown in Figures 15 and 16. Ammonia is then released, yielding the hydrogen-bonded complex PH [Xan-(N3) 3 3 3 NH3 3 3 3 H2O]. The overall activation energy is 144 kJ mol-1 at the G3MP2 level of theory. Figure 16 shows a comparison of the reaction pathways for the deamination of guanine with OH- and with H2O/OH- for pathways G and H. It can be seen from Figure 16 that the addition of a water molecule results in a slightly lower overall barrier for deamination. Table 8. Gas-Phase Deprotonation Enthalpies [PA(A-)] of Guaninea (in kJ mol-1) at 298.15 K level/basis set
a
Gua-(N1H)
Gua-(N10H)
HF/6-31G(d)
1465
1451
MP2/6-31G(d) B3LYP/6-31G(d)
1444 1461
1438 1443
B3LYP/6-31þG(d)
1409
1394
G3MP2
1414
1405
G4MP2
1415
1405
The gas-phase deprotonation reaction, AH f A- þ Hþ.
Figure 13. Comparison of Cyt-(N7H) 3 3 3 H2O complex and Gua-(N10H) 3 3 3 H2O complex.
In summary, pathways G and H show that one additional molecule of water with OH- reduces the activation energy of the rate-determining step significantly. This is due to the fact that the water molecule can stabilize the transition state. The overall activation energies for pathways G and H are 200 and 144 kJ mol-1 at G3MP2, respectively, which are comparable to the overall activation energy for cytosine deamination.50 The most likely mechanism for the deamination of guanine is pathway H, with an overall activation energy of 144 kJ mol-1 at G3MP2, which is about 30 kJ mol-1 higher than the computed barrier for cytosine (115 kJ mol-1).50 3.5. Thermodynamic Properties for the Deamination Reaction of Guanine. The thermodynamic properties for deamination reaction of guanine with H2O, OH-, H2O/OH-, and GuaHþ with H2O are available in the Supporting Information. All of the reactions are found to be exothermic and exergonic at all levels of theory and basis sets. 3.5.1. Thermodynamic Results for the Reaction of Guanine with H2O. Formation of the Xan 3 3 3 NH3 complex is found to be exothermic and exergonic for all levels of theory and basis sets (with enthalpy values of -15.7, -15.1, and -16.4 kJ mol-1 at G3MP2, G4MP2, and CBS-QB3, respectively). The difference between the enthalpy results does not exceed 1 kJ mol-1. The Gibbs free energies (ΔG) of reaction at G3MP2, G4MP2, and CBS-QB3 are -18.3, -17.5, and -18.7 kJ mol-1, respectively. The enthalpy difference for the formation of separated products is found to be endothermic at the Gaussian-n theories (13.6 18.2 kJ mol-1). 3.5.2. Thermodynamic Results for the Reaction of Protonated Guanine (GuaHþ) with H2O. The enthalpy (ΔH) of reaction for the formation of the Xan 3 3 3 NH4þ complex is found to be exothermic and exergonic at all levels of theory (with enthalpies of -88.9 and -91.3 kJ mol-1 at G3MP2 and G4MP2, respectively). The MP2/6-31G(d) enthalpy (-91.9 kJ mol-1) is in better agreement with the G3 and G4 theories than HF and B3LYP. The enthalpy difference between separated reactant [GuaHþ(N10) þ H2O] and product (Xan þ NH4þ) indicates that this reaction is exothermic and exergonic at all levels of theory (with enthalpies from -57.8 to -55.8 kJ mol-1 at G3MP2 and G4MP2, respectively). Deamination of GuaHþ(N10) with H2O to form a xanthine and ammonium is less exothermic and exergonic than for the formation of the complex,
Figure 14. Optimized structures along pathways G for the deamination of guanine with H2O/OH-. 2073
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Figure 15. Optimized structures along pathway H for the deamination of guanine with H2O/OH-.
Table 9. Activation Energies, Enthalpies of Activation, and Gibbs Free Energies of Activation for the Deamination of Guanine with H2O/OH- (in kJ mol-1) at 298.15 K (Pathway G)a
Figure 16. Comparison of pathway F for the deamination of guanine with OH- (dashed line), pathway G for the deamination of guanine with H2O/OH- with a direct 1,3-proton shift (dotted line), and pathway H for the deamination of guanine with H2O/OH- with a 1,3-proton shift mediated by a single water molecule (solid line). Relative energies (in kJ mol-1) are at the G3MP2 level of theory.
HF/ 6-31G(d)
MP2/ 6-31G(d)
B3LYP/ 6-31G(d)
B3LYP/ 6-31þG(d)
G3MP2
ΔEa,TS1G
186
165
152
136
139
ΔHqTS1G
182
157
145
131
134
ΔGqTS1G
191
165
152
143
143
ΔEa,TS2G
136
116
88
62
94
ΔHqTS2G
125
105
76
48
93
ΔGqTS2G
126
106
78
54
95
Barriers were calculated from the Gua 3 3 3 H2O/OH- complex as defined in Figures 14 and 16. a
Table 10. Activation Energies, Enthalpies of Activation, and Gibbs Free Energies of Activation for the Deamination of Guanine with H2O/OH- (in kJ mol-1) at 298.15 K (Pathway H)a HF/6-31G(d) B3LYP/6-31G(d) B3LYP/6-31þG(d) G3MP2
Figure 17. Comparison of the Cyt-(N7H) 3 3 3 H2O 3 3 3 H2O and Gua-(N1H) 3 3 3 H2O 3 3 3 H2O complexes.
due to a lack of hydrogen bonding in the separated species. The enthalpies (ΔH) of reaction for the formation of Xan 3 3 3 NH4þ from the GuaHþ(N3) 3 3 3 H2O complex is found to be exothermic and exergonic at all levels of theory (-8.0 kJ mol-1 at G3MP2). 3.5.3. Thermodynamic Results for the Reaction of Guanine with OH-. Reaction of guanine with OH- yields two possibilities for the separated products, either the xanthine anion and ammonia or xanthine and the amide anion (azanide). These are shown in Figure 1. Deamination of guanine with OH- to produce the Xan-(N3) 3 3 3 NH3 complex is found to be exothermic and exergonic at all levels of theory and basis set. The
ΔEa,TS1H
120
112
114
107
ΔHqTS1H
119
112
115
103
ΔGqTS1H
129
125
125
117
ΔEa,TS2H
105
47
46
54
ΔHqTS2H
96
31
34
52
ΔGqTS2H
106
37
46
58
a Barriers were calculated from the Gua 3 3 3 H2O/OH- complex as defined as Figures 15 and 16.
enthalpies of reaction are from -35.0 to -34.7 kJ mol-1 at G3MP2 and G4MP4, respectively. The enthalpy difference between reactants and separated products indicates that the conversion process is exothermic at the Gaussian-n theories (-39.4 to -40.9 kJ mol-1). Formation of the separated products Xan and NH2- is found to be endothermic and endergonic at all levels of theory to the highly localized negative charge of NH2- anion (unstable strong base). Addition of diffuse functions [B3LYP/6-31þG(d)] improves agreement with the Gaussian-n theories for the reaction Gua þ OH- f Xan þ NH2-. 3.5.4. Thermodynamic Results for the Reaction of Guanine with H2O/OH-. Three possibilities for the separated products, Xan- þ NH3 þ H2O, Xan þ H2O þ NH2-, and Xan þ NH3 þ 2074
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The Journal of Physical Chemistry A OH-, were considered, as shown in Figure 1. The deamination reaction of guanine to produce the Xan-(N3) 3 3 3 NH3 3 3 3 H2O complex is found to be exothermic and exergonic at all levels of theory and basis sets, with enthalpies of -57.0 kJ mol-1 for Gua 3 3 3 H2O 3 3 3 OH- complex f Xan-(N3) 3 3 3 NH3 3 3 3 H2O complex and -21.9 kJ mol-1 for Gua-(N1H) 3 3 3 H2O 3 3 3 H2O complex f Xan-(N3) 3 3 3 NH3 3 3 3 H2O complex at G3MP2. The B3LYP/6-31þG(d) enthalpy (-59.5 kJ mol-1) for Gua 3 3 3 H2O 3 3 3 OH- complex f Xan-(N3) 3 3 3 NH3 3 3 3 H2O complex is in better agreement with the G3 theories than the HF and B3LYP levels of theory using 6-31G(d). A comparison of the Gibbs free energies of reaction shows that the addition of diffuse functions is essential, since the B3LYP/6-31þG(d) (-58.1 kJ mol-1) for Gua 3 3 3 H2O 3 3 3 OH- complex f Xan-(N3) 3 3 3 NH3 3 3 3 H2O complex results are in more reasonable agreement with Gaussian-n theories than those obtained using B3LYP/631G(d) (-75.9 kJ mol-1). The MP2 enthalpy (-30.4 kJ mol-1) for Gua-(N1H) 3 3 3 H2O 3 3 3 H2O complex f Xan-(N3) 3 3 3 NH3 3 3 3 H2O complex is in better agreement with the results obtained with G3 theories than those of HF and B3LYP. Formation of the separated products (Gua þ H2O þ OH- f Xan þ H2O þ NH2-) is found to be endothermic and endergonic at all levels of theory. This is due to the highly resonance-stabilized xanthine anion, which has a highly delocalized negative charge, versus the highly localized unstable NH2anion.
4. CONCLUSIONS A comprehensive investigation was conducted to obtain possible mechanisms involved in the deamination reaction of guanine with H2O, OH-, H2O/OH-, and GuaHþ with H2O. Optimized geometries were determined at the RHF, MP2, B3LYP, and higher level Gaussian-n theories such as G3MP2, G3MP2B3, G4MP2, and CBS-QB3. Activation energies, enthalpies, and Gibbs free energies were calculated for each reaction pathway. Intrinsic reaction coordinate IRC analysis was carried out for all transition state structures to obtain the complete reaction pathway. Two pathways (A and B) were found for the deamination reaction of guanine with water, and three pathways (C, D, and E) were found for the reaction of GuaHþ with H2O. There is a high activation energy barrier for the addition of H2O to the protonated guanine complex and a similar high activationenergy barrier for the subsequent 1,3-proton shift that leads to the decomposition of the tetrahedral intermediate. Deamination with OH- has significantly lower activation energy than for the reaction with water. However, the deprotonation of guanine by OH- is very exothermic because the anion formed by the loss of a proton is highly resonance-stabilized. The computed activation energy for the rate-determining step of guanine with OH- is 155 kJ mol-1 at the G3MP2 level of theory, which is slightly higher compared to 148 kJ mol-1 for cytosine.37 The deamination reaction of guanine with H2O/OH- was also studied, with two pathways found for this reaction (G and H). The lowest calculated overall activation energy is 144 kJ mol-1 at the G3MP2 level of theory obtained when the 1,3-proton shift is mediated by a single water molecule. Additional water molecules or the use of continuum models are likely to further lower these barriers, as was shown for the acid-catalyzed hydrolysis of formamide.51-53 For example, at B3LYP/6-31þG(d) (results not included) the overall barriers, 178, 159, and 152 kJ mol-1, for the reaction of Gua with 2H2O, 3H2O, and 4H2O, respectively,
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are lower than with a single water (227 kJ mol-1). These overall activation energies are, however, still higher than for the reaction with H2O/OH-.
’ ASSOCIATED CONTENT
bS
Supporting Information. Full geometries and energies of all structures are reported. This material is available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION Corresponding Author
*Tel.: (709) 864-8609. Fax: (709) 864-3702. E-mail: rpoirier@ mun.ca.
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