Interaction of Adenine Adducts with Thymine: A Computational Study

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J. Phys. Chem. B 2007, 111, Interaction of Adenine Adducts with Thymine: A Computational Study Prabhat K. Sahu, Chang-Wang Kuo, and Shyi-Long Lee* Department of Chemistry and Biochemistry,
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J. Phys. Chem. B 2007, 111, Interaction of Adenine Adducts with Thymine: A Computational Study Prabhat K. Sahu, Chang-Wang Kuo, and Shyi-Long Lee* Department of Chemistry and Biochemistry, National Chung Cheng UniVersity, Chia-Yi, 621 Taiwan ReceiVed: October 18, 2006; In Final Form: December 6, 2006 The existence of DNA adducts bring the danger of carcinogenesis because of mispairing with normal DNA bases. 1,N 6 -ethenoadenine adducts (ɛa) and 1,N 6 -ethanoadenine adducts (EA) have been considered as DNA adducts to study the interaction with thymine, as DNA base. Several different stable conformers for each type of adenine adduct with thymine, [ɛa(1)-t(i), ɛa(2)-t(i), ɛa(3)-t(i) and EA(1)-T(I), EA(2)-T(I), EA(3)-T(I)] and [ɛa(1)-t(ii), ɛa(2)-t(ii), ɛa(3)-t(ii) and EA(1)-T(II), EA(2)-T(II), EA(3)-T(II)], have been considered with regard to their interactions. The differences in their geometrical structures, energetic properties, and hydrogen-bonding strengths have also been compared with Watson-Crick adenine-thymine base pair (A-T). Single-point energy calculations at MP2/ G** levels on B3LYP/6-31+G* optimized geometries have also been carried out to better estimate the hydrogen-bonding strengths. The basis set superposition error corrected hydrogen-bonding strength sequence at MP2/ G**//B3LYP/6-31+G* for the most stable complexes is found to be EA(2)-T(I) (15.30 kcal/mol) EA(1)-T(II) (14.98 kcal/mol) EA(3)-T(II) (14.68 kcal/mol) ɛa(2)-t(i) (14.54 kcal/mol) ɛa(3)-t(ii) (14.22 kcal/mol) ɛa- (3)-T(II) (13.64 kcal/mol) A-T (13.62 kcal/mol). The calculated reaction enthalpy value for ɛa(2)-t(i) is kcal/mol, which is the highest among the etheno adduct-thymine complexes and about 1.55 kcal/ mol more than those obtained for Watson-Crick A-T base pair and the reaction enthalpy value for EA(1)- T(II) is kcal/mol, which is highest among the ethano addcut-thymine complexes and about 1.72 kcal/ mol more than those obtained for Watson-Crick A-T base pair. The aim of this research is to provide fundamental understanding of adenine adduct and thymine interaction at the molecular level and to aid in future experimental studies toward finding the possible cause of DNA damage. Introduction Endogenous lipid peroxidation products such as malondialdehyde, crotonaldehyde, and 4-hydroxy-2-nonenal are particularly potent in forming adducts during periods of oxidative stress. 1 The type and quantity of fatty acids in the diet is also of significance in those trans-fatty acids, and their metabolic derivatives seem to lead to excessive formation of adducts. The initial identification of exocyclic adducts was in the 1960s; numerous studies have been reported on the identification, chemistry, and biology of various exocyclic adducts originating from both environmental and industrial sources 2 [1,N 2 -ethenodeoxyguanosine, N 2,3-ethenodeoxyguanosine (ɛdg), 3,N 4 - ethenodeoxycytidine (ɛdc), and 1,N 6 - ethenodeoxyadenosine (ɛda) produced by chloroethylene oxide and chloroacetaldehyde, reactive metabolites of the human carcinogen, vinyl chloride]. ɛda and ɛdc have also been identified in mice treated with vinyl carbamate or ethyl carbamate. 3 Recently, these two adducts were shown to exist in liver DNA of untreated rats and humans, 4 suggesting their formation from certain endogenous sources. In fact, Ghissassi et al. 5 have shown that lipid peroxidation products cause the formation of ɛda and ɛdc. The levels of DNA adducts in human leucocytes has been found to vary with a number of lifestyle, environmental, and chemical-exposure factors. Cancers with poorly defined etiology may be explained once DNA adducts are identified. It has been reported that the existence of DNA adducts bring the danger of carcinogenesis because of mispairing with normal DNA bases. 4 Exocyclic DNA adducts are a unique class of ring-extended modifications 6 formed by a * Corresponding author. wild range of chemicals. DNA adducts play a role in vinyl chloride induced tumorigenisis. 7 DNA adducts are also implicated in many types of human cancer, especially where persistent oxidative stress leads to malignancy by increasing mutations and genomic instability at the DNA level. The detection of DNA adducts as promutagenic markers enables, in some patients, an understanding of cancer risk. It also defines and promotes active intervention measures aimed at reducing exposure to the offending chemicals or moderation of the endogenous processes responsible for some adducts. This is particularly so where the level of and destructive activity of metal adducts can be reduced by the use of nutritionally important. It would be a great subject of interest to study the interaction of 1,N 6 -ethenoadenine adducts (ɛa) and 1,N 6 -ethanoadenine adducts (EA) as DNA adducts and thymine as nucleic acid base. 1,N 6 -Ethanoadenine adducts differ from etheno adducts by the change of a double to a single bond in a five-member exocyclic ring and are formed by chloroethyl nitrosoureas, which are used in cancer therapy. 8 The intrinsic mutagenic potential of 1,N 6 - ethenoadenine adduct has been investigated in Esherichia coli (E. coli) and mammalian cells. 9 Experimentally, it has been shown that ɛa is highly mutagenic. 10 We would like to investigate the changes for the gas phase of interaction in ɛa-t and EA-T complexes, including different structures. It may provide a possible cause for DNA damage and aid in future experimental studies toward the understanding of the adenine adduct-thymine complexes (ɛa-t, EA-T). In our work, we have considered many different positions of interactions between adenine adducts and thymine, [ɛa(1)-t(i), ɛa(2)-t(i), ɛa(3)-t(i) and EA(1)-T(I), EA(2)-T(I), EA /jp066856t CCC: $ American Chemical Society Published on Web 02/28/2007 2992 J. Phys. Chem. B, Vol. 111, No. 11, 2007 Sahu et al. SCHEME 1: Interacting Parts Considered for the Adenine Adducts (EA and EA) and Thymine in Our Study (3)-T(I)] and [ɛa(1)-t(ii), ɛa(2)-t(ii), ɛa(3)-t(ii) and EA- (1)-T(II), EA(2)-T(II), EA(3)-T(II)] (Scheme 1), and compared the difference in their geometrical structures, energetic properties, and hydrogen-bonding strengths with Watson-Crick adenine-thymine base pair (A-T). It is also insightful since it provides a fundamental understanding of adenine adduct and thymine interaction at the molecular level. In recent years, so as to understand the various biochemical processes including point mutation, several studies on tautomeric equilibria of nucleic acid bases and their interaction with ions in the gas phase have been reported However, the biochemical process is predominantly a solution-based discipline with water providing the ubiquitous solvent. We are aware of such a solvent effect, which will be the aim of our future projects. Computational Methods The geometry and harmonic vibrational frequencies of ɛa, EA, thymine, and the resulted different possible geometries for ɛa-thymine complexes and EA-thymine complexes have been calculated using density functional theory (DFT) method with the Pople type split valence basis set (6-31+G*). For hydrogenbonded systems, it is expected that both diffuse and polarization function are necessary in the basis set. B3LYP is chosen as density functional for this study. This is a hybrid functional consisting of Becke s exchange functional, the Lee-Yang- Parr correlation functional, and a Hartree-Fock exchange term. DFT has been successfully used to study hydrogen-bonded complexes, even the most weakly bound systems. 32 Besides, previous DFT studies 29-31,33 clarified that one has to apply gradient correction in both the exchange and the correlation part of the potential to get meaningful results in the intermolecular framework. Hybrid DFT functionals, such as B3LYP, by their very nature, already include a part of correct asymptotics via Hartree-Fock exchange, which improves the overall asymptotic behavior of these functionals. Single-point energy calculations at the MP2/ G** levels on B3LYP optimized geometries have also been carried out to better estimate the hydrogenbonding strengths. The calculated hydrogen-bonding energies are corrected for the basis set superposition error (BSSE), using counterpoise method. 34 The electronic structure calculations have been performed using the GAUSSIAN 03 program. 35 Results and Discussion (a) Optimized Geometries Parameters for DNA Adduct- Thymine Complexes. The B3LYP/6-31+G* optimized structure for the etheno adenine-thymine(i) complexes are shown in Figure 1a-c, whereas the ethano adenine-thymine(i) complexes are shown in Figure 2a-c. Optimized structures of etheno adenine-thymine(ii) and ethano adenine-thymine(ii) complexes are shown in Figure 3a-c and Figure 4a-c, respectively. The optimized parameters for the Watson-Crick A-T complex and corresponding monomers using the B3LYP/6-31+G* method have been computed (cf. Suppporting Information Table 1a). A great deal of experimental as well as theoretical work has been carried out to investigate the structure and energetics of the A-T base pair so as to determine the effects of Watson-Crick type hydrogen bonding and its tautomeric transitions on the vibrational spectra of the nucleic acid bases, adenine and thymine. Since we are going to compare the differences in the geometrical structures, energetic properties, and hydrogen-bonding strengths of our current study for the interaction of adenine adducts, ɛa and EA with thymine, we would like to compare our computed structural parameters for A-T base pair, with reference to previous experimental and theoretical observations 11,36-42 (cf. Supporting Information Table 1b). The computed hydrogen bond lengths show the notorious discrepancy with experimental values. The source of divergence seems to be the molecular environment (water, sugar hydroxyl groups, and counter ions) of the base pairs in the crystals studied experimentally. This has been missing, so far in all theoretical models; however, by using B3LYP/6-31+G*, our computed data exhibit superior results to those obtained with HF methods and comparative to those obtained with previous DFT study. 11,41,42 The calculated geometry parameters for the complexes ɛa(1)-t(i), ɛa(2)-t(i), and ɛa(3)-t(i) and the corresponding monomers ɛa and T (cf. Supporting Information Interaction of Adenine Adducts with Thymine J. Phys. Chem. B, Vol. 111, No. 11, Figure 1. (a, top) Optimized structure of ɛa(1)-t(i) complex. (b, middle) Optimized structure of ɛa(2)-t(i) complex. (c, bottom) Optimized structure of ɛa(3)-t(i) complex. Table 2a) reveal that the bond length N 16 -H 28, which is involved in hydrogen bonding for all three complexes ɛa(1)- T(I), ɛa(2)-t(i), and ɛa(3)-t(i), is observed to increase around 0.02 Å as compared to that for the thymine monomer. In the ɛa(2)-t(i) complex, the bond length N 1 -H 15 is involved in second hydrogen bonding also found to be Å as compared to those of Å for the ɛa monomer. The bond angle C 18 N 16 C 17 of thymine monomer is found to be decreased from to 126.8, to 127.0, and to for all three complexes ɛa(1)-t(i), ɛa(2)-t(i), and ɛa(3)-t(i), after complexation, respectively. Conversely, the bond angles C6N7C8, C11N13C14, and C2N4C5 are found to be increased slightly for ɛa(1)-t(i), ɛa(2)-t(i), and ɛa(3)-t(i), respectively, and C14N1C2 found to be decreased 1 as compared to those of the ɛa monomer. The calculated geometry parameters for the complexes EA(1)-T(I), EA(2)-T(I), and EA(3)-T(I) and the corresponding monomers EA and T (cf. Supporting Information Table 2b) also show that the bond length Figure 2. (a, top) Optimized structure of EA(1)-T(I) complex. (b, middle) Optimized structure of EA(2)-T(I) complex. (c, bottom) Optimized structure of EA(3)-T(I) complex. N 16 -H 28, involved in hydrogen bonding for all three complexes EA(1)-T(I), EA(2)-T(I), and EA(3)-T(I), is observed to be increased around 0.023, 0.026, and Å, respectively, as compared to that of the thymine monomer. In the EA(1)-T(I) complex, the bond lengths C6-N7, N7-C8, and C17-O29 are also found to be slightly increased compared to bare EA and thymine, respectively. In the EA(2)-T(I) complex, the bond length N1-H15, which is also involved in second hydrogenbonding, was found to be Å as compared to that of Å for the EA monomer. After complexation, the bond angle C 18 N 16 C 17 of the thymine monomer is found to be decreased from to 126.8, to 126.9, and to for all three complexes EA(1)-T(I), EA(2)-T(I), and EA(3)-T(I), respectively. Conversely, the bond angles C6N7C8, C11N13C14, and C2N4C5 are found to be increased slightly for EA(1)- 2994 J. Phys. Chem. B, Vol. 111, No. 11, 2007 Sahu et al. Figure 3. (a, top) Optimized structure of ɛa(1)-t(ii) complex. (b, middle) Optimized structure of ɛa(2)-t(ii) complex. (c, bottom) Optimized structure of ɛa(3)-t(ii) complex. T(I), EA(2)-T(I), and EA(3)-T(I), respectively, and C14N1C2 for EA(2)-T found to be decreased 0.6 as compared to bare EA. The calculated geometry parameters for the complexes ɛa- (1)-T(II), ɛa(2)-t(ii), and ɛa(3)-t(ii) and the corresponding monomers ɛa and T (cf. Supporting Information Table 2c) exhibit that the bond length N 20 -H 24, involved in hydrogen bonding for all three complexes ɛa(1)-t(ii), ɛa(2)-t(ii), and ɛa(3)-t(ii), is observed to increase around 0.021, 0.015, and Å, respectively, as compared to that of the thymine(ii) monomer. In ɛa(1)-t(ii) complex and ɛa(2)-t(ii) complex, the bond length C18-O21 is found to be and Å, respectively, compared to Å of bare thymine. In ɛa(3)- T(II) complex, the bond lengths C18-O21 and C2-N4 are found to be and Å, compared to and Å of bare thymine(ii) and ɛa, respectively. After complexation, the bond angle C 23 N 20 C 18 of the thymine monomer is found to be decreased from to 123.2, to 122.9, and to for all three complexes ɛa(1)-t(ii), ɛa(2)-t(ii), and ɛa(3)- Figure 4. (a, top) Optimized structure of EA(1)-T(II) complex. (b, middle) Optimized structure of EA(2)-T(II) complex. (c, bottom) Optimized structure of EA(3)-T(II) complex. T(II), respectively. Conversely, the bond angles C6N7C8, C11N13C14, and C2N4C5 are found to increase around 1.0 for ɛa(1)-t(ii), ɛa(2)-t(ii), and ɛa(3)-t(ii), respectively. The calculated geometry parameters for the complexes EA(1)-T(II), EA(2)-T(II), and EA(3)-T(II) and the corresponding monomers EA and T(II) (cf. Supporting Information Table 2d) show that the bond length N 20 -H 24, involved in hydrogen bonding for all the three complexes EA(1)-T(II), EA- (2)-T(II), and EA(3)-T(II), is observed to increase around 0.022, 0.019, and Å, respectively, as compared to that of the thymine(ii) monomer. After complexation, the bond angle C 23 N 20 C 18 of the thymine monomer is found to decrease from to 123.3, to 122.8, and to for all three complexes EA(1)-T(II), EA(2)-T(II), and EA(3)-T(II), respectively. Conversely, the bond angles C6N7C8, C11N13C14, and C2N4C5 are found to increase 1.0 for EA(1)-T(II), EA- (2)-T(II), and EA(3)-T(II), respectively. Interaction of Adenine Adducts with Thymine J. Phys. Chem. B, Vol. 111, No. 11, TABLE 1: Hydrogen Bond Lengths (Å) and Bond Angles (deg) for Adenine Adduct-Thymine Complexes Using B3LYP/6-31+G* parameter ɛa(1)-t(i) EA(1)-T(I) parameter ɛa(1)-t(ii) EA(1)-T(II) N7-H N7-H H31-O H31-O N4-H N7H28N N7H24N C8H31O C8H31O N4H30C parameter ɛa(2)-t(i) EA(2)-T(I) parameter ɛa(2)-t(ii) EA(2)-T(II) N13-H N13-H H15-O H12-O N13H28N N13H24N N1H15O C11H12O parameter ɛa(3)-t(i) EA(3)-T(I) parameter ɛa(3)-t(ii) EA(3)-T(II) N4-H N4-H H3-O H3-O N4H28N N4H24N C2H3O C2H3O However, significant changes in the dihedral angles for ethano-adenine-thymine complex (cf. Supporting Information Table 2b,d) have also been observed after complexation, whereas, for the etheno-adenine adduct, the dihedral bond angles remain unaltered (cf. Supporting Information Table 2a,c). Due to the presence of the more flexible exocyclic ring including four hydrogen atoms in the ethano-adenine adduct, thymine acts on ring accessibly, as a result of the dihedral angles; C6N7C8C9, N7C8C9N10, H31C8C9N10, H32C9C8N7, H33C8C9N10, and H34C9C8N7 have remarkable changes as compared to bare EA, after complexation with thymine (cf. Supporting Information Table 2b,d). (b) Hydrogen-Bonding Parameters for DNA Adduct- Thymine Complexes. The optimized hydrogen bond distances and bond angles for the adenine adduct and thymine complexes, [ɛa(1)-t(i), ɛa(2)-t(i), ɛa(3)-t(i) and EA(1)-T(I), EA- (2)-T(I), EA(3)-T(I)] and [ɛa(1)-t(ii), ɛa(2)-t(ii), ɛa(3)- T(II) and EA(1)-T(II), EA(2)-T(II), EA(3)-T(II)], are cited in Table 1. The hydrogen bond is a unique phenomenon in structural chemistry and biology. Its fundamental importance lies in its role in molecular association and is considered as an important factor in stabilizing bimolecular structures. From Table 1, it can be observed that the hydrogen bond lengths N7- H28 and O29-H31 in ɛa(1)-t(i) complex are found to be and Å, respectively, and in EA(1)-(T) complex, and Å, respectively. For ɛa(1)-t(i) and EA(1)- T(I) complexes, the bond angle N7H28N16 is found to be and 164.7, whereas the bond angle C8H31O29 is found to be and 133.7, respectively. The hydrogen bond lengths N13-H28 and O21-H15 are found to be and Å in ɛa(2)-t(i) complex and and Å in EA(2)-T(I) complex,respectively.thecorrespondingbondangles N13H28N16 (175.2 and ) and N1H15O21 (161.9 and ) for these complexes are found to be nearly the same. In ɛa(3)- T(I) and EA(3)-T(I) complexes, the hydrogen bond lengths N4-H28 and O29-H3 are found to be and Å, and and Å, respectively, and the corresponding bond angles are found to be N7H28N16 (163.7 and ) and C8H31O29 (135.3 and ), respectively. On comparing the ɛa(1)-t(i), ɛa(2)-t(i), and ɛa(3)-t(i) complexes, the hydrogen bond lengths (N-H N and N-H O) found for ɛa- (2)-T(I) complex were observed to be shorter, having more linear corresponding bond angles, indicating strong interaction among the three different complexes. On the other hand, similar to the etheno-adenine adduct-thymine complex, among the three different ethano-adenine adduct-thymine complexes EA- (1)-T(I), EA(2)-T(I), and EA(3)-T(I), the EA(2)-T(I) complex has shorter hydrogen bond lengths (N-H N and N-H O) and the corresponding bond angles are more linear, associated with strong interaction (details about the interaction energy will be discussed in the next section). Table 1 also depicts that the hydrogen bond length N7-H24 is found to be approximately the same (1.881 and Å) for the ɛa(1)-t(ii) and EA(1)-T(II) complexes, respectively, whereas O29-H31 is found to be Å for ɛa(1)-t(ii) complex and N4-H30 is found to be Å for EA(1)-T(II) complex. The corresponding bond angles N7H24N20 are and for ɛa(1)-t(ii) and EA(1)-T(II) complexes, respectively, whereas C8H31O29 is found to be for ɛa(1)-t(ii) and N4H30C23 is found to be for EA- (1)-T(II). In ɛa(2)-t(ii) and EA(2)-T(II) complexes, the hydrogen bond lengths are N13-H24 (2.024 and Å, respectively) and O21-H12 (2.219 and Å, respectively) and the corresponding bond angles N13H24N20 (169.5 and 170.3, respectively) and C11H121O21 are found to be approximately the same (146.2 and ). The hydrogen bond lengths in ɛa(3)-t(ii) and EA(3)-T(II) complexes are N4- H24 (1.903 and Å, respectively) and O21-H3 (2.396 and Å, respectively) and the corresponding bond angles are N4H24N20 (167.8 and 169.1, respectively) and C2H3O21, found to be and 128.0, respectively. On comparing the three different complexes ɛa(1)-t(ii), ɛa(2)-t(ii), and ɛa- (3)-T(II), it has been observed that, out of the two hydrogen bond lengths, N-H N is shorter and has more linear corresponding bond angles as compared to C-H OdC. Similar observation is also found for the three different EA(1)-T(II), EA(2)-T(II), and EA(3)-T(II) complexes. More details regarding strong or weak interaction will be discussed in next section. (c) Energetics and Hydrogen-Bonding Energy Strength for DNA Adduct-Thymine Complexes. The total energy and the BSSE corrected hy
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