(PDF) … ring puckering, anti-syn interconversion and intramolecular interactions on N-glycosidic bond cleavage in 3-methyl-2′-de

J. Iran. Chem. Soc., Vol. 8, No. 4, December 2011, pp. 908-918. JOURNAL OF THE Iranian Chemical Society Effects of Sugar Ring Puckering, Anti-Syn Interconversion and Intramolecular Interactions on N-Glycosidic Bond Cleavage in 3-Methyl-2´-deoxyadenosine and 2´- Deoxyadenosine D A. Ebrahimi*, M. Habibi-Khorassani and S. Bazzi Department of Chemistry, University of Sistan and Baluchestan, P.O. Box 98135-674, Zahedan, Iran SI (Received 9 December 2010, Accepted 11 February 2011) The effects of structural parameters and intramolecular interactions on N-glycosidic bond length in 3-methyl-2´- deoxyadenosine (3MDA) and 2´-deoxyadenosine (DA) were investigated employing quantum mechanical methods. All of calculations were performed at B3LYP/6-311++G** level in the gas phase. The N-glycosidic bond length strongly depends on sugar configuration; it is shorter in syn conformation relative to anti in many cases where they have the same sugar ring configuration. The sugar conformation can influence the N-glycosidic bond through interaction with the O4´ atom. The impact of intramolecular improper hydrogen bonds and H-H bonding interactions on N-glycosidic bond length was investigated in DA and ive 3MDA and their modeled structures. Improper hydrogen bonds decrease N-glycosidic bond length while H-H bonding interactions increase it. Keywords: 3-Methyl-2´-deoxyadenosine, N-Glycosidic bond, Sugar ring puckering, Anti-syn interconversion, DNA repair enzyme, Improper hydrogen bond ch INTRODUCTION methyl-2´-deoxyadenosine (3MDA) in human cells. Methylated nucleotides and N-glycosidic bond cleavage have Deoxyribonucleic acid (DNA) damage is very frequent and been studied by different authors from both the experimental Ar appears to be a fundamental problem for life [1]. The cleavage [7-22] and theoretical [23-26] points of view. of the N-glycosidic bond in deoxynucleosides and nucleosides The inherent flexibility of sugar introduces major is a common reaction in DNA damage and repair [2], toxicity structural changes and causes important bearing on the mechanisms [3], and nucleobase salvage [4-6]. Depurination is biological function in the naturally occurring nucleic acids a process in which the purine base (adenine or guanine) is [27-29]. The two standard forms of right-handed DNA are removed from the deoxyribose sugar by hydrolysis of N- principally defined by the sugar geometry; particularly north glycosidic bond. Most damaged bases can be removed and (C(3´)-endo) is a characteristic of A-DNA whereas south replaced in a process that begins with a glycosylase. For (C(2´)-endo) is a characteristic of B-DNA [30]. The example, alkyl adenine DNA glycosidase (AAG) is conformational properties of deoxyadenosine (DA) and responsible for recognizing and initiating the repair of a broad 3MDA have been studied by different researchers [31-34]. range of alkylated purines (damaged bases) including 3- In the present study, the impacts of conformational changes, including sugar ring puckering and anti-syn *Corresponding author. E-mail:

interconversion that lead to different intramolecular www.SID.ir Ebrahimi et al. 6 NH2 interactions, on the N-glycosidic bond of 3MDA and DA have been investigated by quantum mechanical methods. The 6 7N 5 correlation between electronic properties and the N-glycosidic N1 bond strength has been examined by means of natural bond H 8 orbital (NBO) and atoms in molecules (AIM) [36] analyses. A 2 N 4 comparison of the most stable conformation of 3MDA with 9 N 3 that of DA may be useful for evaluating the role of 4' X conformational changes in alkylated base recognition by DNA Y O repair enzymes. D 4' H 3' 2' H 1' METHODS AND MODEL 4"H 3' H 1' Z 2" H DA and 3MDA can be modeled by replacing the sugar phosphate backbone and 3´-hydroxyl group with the hydrogen atoms (Scheme 1). One of the parameters defining the mononucleotide conformation is the dihedral angle about the SI X = H (DA), C 3 3 H 31 H 32 (3MDA); Y = CH2OH; Z = OH H 33 model structures : Y = H; Z = H 5' 5' 3' of N-glycosidic bond between the sugar and base (φO4'C1'N9C8 in 4' 3" Scheme 1). The two possible orientations of the base with Base Base Base respect to the sugar are termed syn (φO4'C1'N9C8 ≈ 180) and anti (φO4'C1'N9C8 ≈ 60) that are denoted 1 and 2 in DA, 1´ and 2´ in O O O model DA, m1 and m2 in 3MDA, and m1´ and m2´ in model ive 3MDA conformations, respectively. Adenosine can exist a b c either in syn (closed) or anti (open) form, and the b b Scheme 1. Atomic numbering of DA, 3MDA, and model interconversion between these two conformations is achieved structures and the twist conformers of sugar ring. by the pivot move around the N-glycosidic bond [37,38]. ch The sugar ring in adenosine may exist in the north type (C(2´)-exo and C(3´)-endo) or south type (C(2´)-endo and Single point calculations were performed on geometries C(3´)-exo) [39,40]. a and b are used for north and south optimized at the above-mentioned level to investigate the conformations, respectively, and c is used for those that cannot dependence of the energy values on the level of calculation. Ar be specified by a or b index (see Scheme 1). Likewise, the The solvent effect was treated by way of a polarizable pseudo-rotation angle P is used to define the conformational continuum model (PCM) calculation using the integral distribution of the sugar ring [40,41]. a conformers comprise equation formalism model (IEFPCM) [44] as implemented in all conformations that occupy the north half of the pseudo- Gaussian03 program package with a dielectric constant of rotational circle (P = 0 ± 90°) and b conformers occupy the 78.39 for H2O. southern half of the circle (p = 180 ± 90°) [40]. The NBO and AIM analyses were performed on the wave All geometries were optimized by the hybrid Hartree Fock functions obtained at 6-311++G** level of theory by NBO3.1 density functional theory RB3LYP in conjunction with the 6- [45] and AIM2000 [46] programs. 311++G** basis set using Gaussian03 program package. Frequency analysis was also performed at the same theoretical RESULTS AND DISCUSSION level. The absence of imaginary frequencies verified that all structures were true minima. The higher-level B3LYP/AUG- The results are presented in two subsections: one cc-pVDZ, MPWPW91/AUG-cc-pVDZ, MPWPW91/6- subsection corresponds to the 3MDA and DA (conformations 311++G**, MP2/AUG-cc-pVDZ, and MP2/6-311++G** are denoted as m1a, m1b, m1c, m2a, and m2b for 3MDA and 909 www.SID.ir Effects of Sugar Ring Puckering, Anti-Syn Interconversion and Intramolecular Interactions 1a, 1b, 2a, and 2b for DA) and the other corresponds to the energies was almost independent of the method and basis set model structures of 3MDA and DA (denoted as m1´a, m1´b, (see Table 1). In discussing the relationship between the m1´c, m2´a, and m2´b for the model 3MDA and 1´a, 1´b, 2´a, relative energies and geometrical parameters, we use the and 2´b for the model DA). Where elongation or contraction results obtained at the B3LYP/6-311++G** level of theory. of bonds due to the intramolecular interaction is reported, the The order of the relative energies in the gas phase was m1´c > lengths of bonds are compared with those in the structures that m1´b > m2´b > m2´a > m1´a at all levels of theory and was are free from that intramolecular interaction. nearly identical to the trend in the solution media (the energy values of m1´c and m1´b are nearly identical in the solution). Model 3MDA As can be seen in Table 1, the range of the relative energies in D The relative energy Erel decreased as the basis set changed the solution (0-2.16 kcal mol-1) is shorter than the range of the from 6-311++G** to AUG-cc-pVDZ. The maximum change relative energies in the gas phase (0-3.65 kcal mol-1). The was equal to 0.61 kcal mol-1 (∼19%) for m2´b. The change in dipole moments calculated at the above-mentioned level are relative energy was ∼5% on changing the method from B3LYP to MPWPW91 that increases to ∼40% on changing from B3LYP to MP2. In any case, the trend in the relative SI also given in Table 1. The overall molecular polarity is expressed as the dipole moment and species with a higher dipole moment become more stable in polar solvents. Thus, of Table 1. The Relative Energies in kcal mol-1 and the Dipole Moments (D) in Debye B3LYP MPWPW91 MP2 D ive Model 3MDA m1´a 0.00 (0.00) 0.00 0.00 0.00 0.00 0.00 2.17 m2´a 2.44 (0.71) 2.00 2.43 1.93 2.54 2.17 5.00 m1´b 3.64 (2.16) 3.32 3.76 3.40 3.90 3.71 2.65 m2´b 3.10 (1.58) 2.60 3.25 2.64 4.08 3.71 4.91 ch m1´c 3.65 (2.08) 3.23 3.76 3.35 3.86 3.62 2.54 Model DA 1´a 0.53 (0.78) 0.54 1.01 0.68 1.14 0.80 3.72 2´a 0.05 (0.11) 0.33 0.15 0.00 0.00 0.00 4.39 Ar 1´b 0.00 (0.20) 0.00 0.00 0.13 0.35 0.00 3.66 2´b 0.83 (0.00) 1.05 1.19 0.91 1.83 1.78 5.37 3MDA m1a 1.10 1.30 1.21 1.43 0.00 0.16 m2a 1.92 1.81 2.00 1.82 2.33 2.13 m1b 2.35 2.28 2.60 2.68 2.16 2.04 m2b 0.00 0.00 0.00 0.00 0.32 0.00 m1c 2.35 2.28 2.60 2.68 2.16 2.04 DA 1a 2.69 2.86 2.88 3.06 3.26 3.62 2a 5.83 6.18 6.02 6.35 6.18 7.58 1b 0.00 0.00 0.00 0.00 0.00 0.00 2b 5.77 5.85 6.08 6.20 6.16 7.29 The italicized values calculated with the AUG-cc-pVDZ basis set and others calculated with 6-311++G** basis set. The data in the parentheses calculated in solution media. 910 www.SID.ir Ebrahimi et al. the maximum difference between the relative energies in the The following is an account of how sugar conformation solution media is lower than the gas phase and corresponds to affects the glycosidic bond. The results of NBO analysis on the conformer that has the maximum dipole moment in each the wave functions obtained at B3LYP/6-311++G** level are category. In the model 3MDA, the highest dipole moment and given in Table 3. The order of occupancy of σ*C1'N9 is m2´a > the largest difference between the relative energies in the gas m1´a > m2´b > m1´b > m1´c, which is similar to the order of phase and the solution media correspond to m2´a. Apart from the bond length. The N-glycosidic bond length increases as the φC4'C1'N9C8 dihedral angle (see Scheme 1), there is a meaningful occupation number of σ*C1'N9 increases, therefore, the impact relationship between the relative energy and sugar of lp(O) → σ*C1'N9 interaction that plays a significant role in the conformation; conformation a, is more stable than b, while c is occupation number of σ*C1'N9 becomes more clear. The lp(O) D in the highest energy level in the model 3MDA. Some → σ*C1'N9 interaction energy E(2) ranges from 1.70 to 13.22 geometrical parameters of different conformations are kcal mol-1. As can be seen in Table 3, the order of E(2) value is presented in Table 2. In both gas phase and solution media the m1´a > m2´a > m2´b > m1´b > m1´c. The E(2) value depends order of N-glycosidic bond length (C1´-N9) is m2a´ > m1´a > m2´b > m1´b > m1´c. Thus, except for φO4'C1'N9C8 dihedral angle, N-glycosidic bond length strongly depends on sugar conformation. As a result, the longest and shortest bonds SI on sugar conformation such that the trend in this value is similar to the trend in N-glycosidic bond length, i.e. a > b > c. Thus, the O4' atom strongly influences the N-glycosidic bond through lp(O) → σ*C1'N9 interaction upon conformational of correspond to a and c conformations, respectively. changes. Table 2. Some Geometrical Parameters (in Å) for the Model and Nonmodel Structures ive 3MDA m1´a m2´a m2´b m1´b m1´c m1a m2a m2b m1c N9-C8 1.392 1.391 1.392 1.393 1.393 1.391 1.395 1.395 1.394 N9-C4 1.372 1.368 1.367 1.376 1.376 1.37 1.367 1.368 1.378 ch N9-C1´ 1.500 1.509 1.498 1.476 1.471 1.498 1.502 1.478 1.469 (N9-C1´) sol 1.499 1.507 1.495 1.475 1.469 C1´-O4´ 1.403 1.392 1.399 1.406 1.407 1.404 1.399 1.411 1.410 C1´-C2´ 1.532 1.541 1.541 1.531 1.547 1.524 1.535 1.534 1.530 Ar C8-H6 1.077 1.077 1.078 1.080 1.080 1.077 1.082 1.081 1.080 C2´-H2´ 1.089 1.091 1.093 1.093 1.091 1.089 1.090 1.089 1.090 C3-H32 1.088 1.090 1.090 1.086 1.085 1.088 1.090 1.090 1.084 DA 1´a 2´a 2´b 1´b 1a 2a 2b 1b N9-C8 1.384 1.382 1.382 1.383 1.383 1.384 1.385 1.384 N9-C4 1.386 1.380 1.378 1.385 1.383 1.379 1.382 1.382 N9-C1´ 1.461 1.482 1.470 1.467 1.467 1.466 1.45 1.457 (N9-C1´) sol 1.462 1.482 1.462 1.466 C1´-O4´ 1.420 1.408 1.416 1.415 1.412 1.422 1.431 1.418 C1´-C2´ 1.545 1.532 1.542 1.548 1.542 1.536 1.535 1.534 C8-H6 1.081 1.078 1.078 1.081 1.081 1.080 1.080 1.081 C2´-H2´ 1.089 1.088 1.093 1.089 1.090 1.089 1.090 1.090 N3-H5´ 0.977 0.961 0.961 0.980 911 www.SID.ir Effects of Sugar Ring Puckering, Anti-Syn Interconversion and Intramolecular Interactions Table 3. The lp(O) → σ*C1'N9 Interaction Energy E(2) in kcal mol-1 and the Occupancy of σ*C1'N9 (×102) Calculated by the NBO Method at the B3LYP/6-311+ + G** Level E(2) nσ* E(2) nσ* 1´b 11.43 6.49 1b 4.87 5.24 2´a 11.94 6.90 2a 8.76 6.09 1´a 7.48 5.96 1a 7.41 6.02 2´b 9.15 5.90 2b 1.49 4.99 D m1´a 13.22 7.88 m1a 13.63 7.98 m2´a 12.70 7.91 m2a 11.14 7.48 m2´b 10.29 6.92 m2b 6.27 5.88 m1´b m1´c 3.87 1.70 5.46 4.98 SIm1b m1c 0.97 0.97 4.91 4.91 of The ρ and ∇2ρ values calculated by the AIM method at proton acceptor (Y) to the remote part of the proton donor (Z- intramolecular bond critical points (BCPs) are given in Table X part of the Z-X-H···Y system). The electron density increase 4. The C-H···H-C, C-H···O, N-C···H-C and C-C···H-C in the remote part of the proton donor leads to the elongation intramolecular interactions are observed in different of bond(s) in the part of the system which in the second step is ive conformations of model 3MDA (see Fig. 1 for two typical accompanied by a structural reorganization of the whole molecular graphs). The ρ and ∇2ρ values calculated at BCPs of proton donor. The net effect of this reorganization is a intramolecular interactions range from 5.406 × 10-3 to 16.978 contraction of the X-H bond with a concomitant increase (blue × 10-3 au and 0.017 to 0.056 au, respectively. shift) in the X-H stretch frequency. The N-C···H-C and C- ch In C-H···O interaction, O4´ is proton acceptor and the C···H-C interactions that are observed in anti conformations nucleobase is proton donor. The contraction of the C-H bond could be considered as electrostatic interactions between C (by 0.002 to 0.005 Å) and a concomitant blue shift (by 37.56 and H atoms that possess disparate charges. to 54.85 cm-1; see Table 5) of the C-H stretching vibrational The N-glycosidic bond in anti conformations of the model Ar frequency can be the consequences of structural reorganization 3MDA (1.498 and 1.509 Å in m2´b and m2´a) is longer than resulting from the elongation of bonds in the remote part of syn (m1b (1.476) and m1a (1.500) Å) when the sugar ring the proton donor (see Table 2). The value of changes is small, configuration is kept constant. Moreover, the O4´···H31-C3 but due to the weakness of such intramolecular interactions, improper hydrogen bond is only observed in syn discussion about these changes is justifiable and confirmed configurations and the C4-N9 bond (in remote part of proton experimentally in these systems [47]. The C-H stretching donor) in syn is longer than anti (by ~0.01 Å). Since the C4- vibrational frequency in model 3MDA conformations is N9 bond elongation is accompanied by the N-glycosidic bond compared with that when the sugar is replaced with the H contraction, the shorter glycosidic bond in syn relative to anti, atom. So, the C-H···O interaction in the model 3MDA can be can partly be attributed to the O4´···H31-C3 improper categorized as an improper hydrogen bond. Hobza [47] has hydrogen bonds. On the other hand, the N-C···H-C and C- investigated the nature of improper hydrogen bonds. C···H-C electrostatic interactions do not have a significant According to the Hobza report, improper blue shifting effect on the N-glycosidic bond length in anti conformations. hydrogen bonding of the type Z-X-H···Y is portrayed by a An H⋅⋅⋅H intramolecular BCP is observed in the molecular two-step process. First, electron density is transferred from the graph obtained from the AIM analysis for each one of m1´a, 912 www.SID.ir Ebrahimi et al. Table 4. The Values of ρBCP ×103 and ∇2ρBCP (in au) Calculated at the BCPs of Intramolecular Interactions ρBCP ∇2ρBCP ρBCP ∇2ρBCP m1´a m1´c O4´-H31 15.176 0.055 O4´-H32 16.978 0.056 H2´-H6 11.047 0.046 H2´-H31 7.097 0.022 C1´-N9 234.506 -0.552 C1´-N9 249.119 -0.636 D m2´a 1´a C2´H32 5.619 0.020 H2´-N3 7.564 0.028 H1"-C3 C1´-N9 m2´b 8.217 230.193 0.030 -0.531 SI H3´-N3 C1´-N9 1´b 10.035 258.205 0.030 -0.683 of H2"-H32 5.406 0.017 H2´-N3 9.943 0.033 H1"-C3 9.012 0.033 H4´-N3 7.102 0.020 C1´-N9 235.690 -0.563 C1´-N9 254.890 -0.660 ive m1´b 2´a O4´-H32 16.112 0.055 H2´-N3 7.953 0.026 H2´-H31 7.448 0.022 C1´-N9 248.306 -0.632 ch C1´-N9 246.098 -0.620 2´b C1´-N9 254.748 -0.670 Ar m2´b, m1´b and m1´c conformers. According to Tables 2 and DA conformations in the gas phase and solution media range 4, the N-glycosidic bond elongation is accompanied by the from 0.00 to 0.83 and 0.00 to 0.78 (in kcal mol-1), respectively. increases in ρH···H in the syn conformations. The range changes slightly from the gas phase to the solution media. The 3MDA conformations are at a lower energy level Model DA in the solution media relative to the gas phase. As seen in Table 1, the difference between the relative The results of NBO analysis at B3LYP/6-311++G** level energies of conformations is lower than that in the model are displayed in Table 3. The lp(O) → σ*C1'N9 interaction 3MDA. So, the trend in the energy values changes a little as energy E(2) ranges from 7.48 to 11.94 kcal mol-1 for different the level changes. The most stable conformation is 1´b that conformations of the model DA (see Table 3). The orders of changes to 2´a at the MPWPW91/AUG-cc-pVDZ and MP2/6- E(2), occupation number of σ*C1'N9, and the N-glycosidic bond 311++G** levels of theory. Herein, the most stable length in the gas phase are 2´a (11.94) > 1'b (11.43) > 2´b conformation is 1´b at the B3LYP/6-311++G** level while it (9.15) > 1´a (7.48 kcal mol-1), 2´a (6.90) > 1´b (6.49) > 1´a is m1´a in the model 3MDA. The relative energies of model (5.96) > 2´b (5.90 e), and 2´a (1.482) > 2´b (1.470) > 1´b 913 www.SID.ir Effects of Sugar Ring Puckering, Anti-Syn Interconversion and Intramolecular Interactions m1b D SI of ive m1′′b Fig. 1. The molecular graphs of m1´b and m1b obtained from AIM analysis at the B3LYP/6- ch 311++G** level of theory. (1.467) > 1´a (1.461 Å), respectively. In the solution media, more than the effect of sugar ring puckering. The N-glycosidic Ar the bond length in 1´b (1.466 Å) is slightly greater than 2´b bond in the anti conformation is longer than syn with the same (1.462 Å) (see Table 3). There are logical relationships sugar ring configuration. between the N-glycosidic bond length, the occupation number The lengths of C-H bonds that interact with the N3 atom of σ*C1'N9, the E(2) value of lp(O) → σ*C1'N9 interaction, and the are shorter than 1.090 Å, but the lengths of other C-H bonds of sugar ring configuration in the model 3MDA conformations. sugar ring are longer than that value in all conformations of However, there is not a meaningful relationship between these the model DA. The contraction of C-H bond and a parameters in the model conformations of DA. The N- concomitant blue shift of the C-H stretching vibrational glycosidic bond length is not in logical relationship with the frequency are consequences of the structural reorganization occupation number of σ*C1'N9, because the conformational resulting from the elongation of bonds in the remote part of changes that lead to different lp(O) → σ*C1'N9 interactions have the proton donor. The C-H stretching vibrational frequency is an ambiguous impact on the N-glycosidic bond length. On the compared with the corresponding value where the sugar ring is other hand, the effect of other parameters, such as rotation replaced with an H atom. The results are in agreement with the around the φO4'C1'N9C8 angle, that leads to different C-H···N intramolecular improper hydrogen bonds. What is the intramolecular interactions, on the N-glycosidic bond length is effect of these interactions on the N-glycosidic bond length. 914 www.SID.ir Ebrahimi et al. Table 5. The Change of X-H Stretching Vibrational Frequency in cm-1 Conformation ν Conformation ν m1´a(C3-H32) 37.56 m2a(C8-H6) -60.77 m1´b(C3-H32) 54.85 m2b(C8-H6) -44.31 m1´c(C3H32) 53.08 m2b(C2´-H2´) 11.27 1a(O5´-H5´) -316.72 1´a(C2´-H2´, C3´-H3´) 38.61 1´b(C2´-H2´) 31.85 1b(N3- H2´,O5´-H2´) 10.74 1´b(C4´-H4´) 43.12 1b(O5´-H5´) -384.89 D 2´a(C2´-H2´) 47.15 2a(C8-H6) 12.96 2´b(C2´-H2") 36.39 2a(C2'-H2´) 6.59 m1b(C3-H32) 18.17 2b(C8-H6) 13.64 m1c(C3-H32) 19.93 SI 2b(C2´-H2´) ν = ν - ν(in the absence of XH⋅⋅⋅Y hydrogen bond). 21.45 of There is a meaningful relationship between the N-glycosidic The results of NBO analysis on the wave functions bond length and the sum of C1´-O4´ and C1´-C2´ bond lengths obtained at B3LYP/6-311++G** level are given in Table 3. in all conformations. The improper hydrogen bonds can affect The trend in the lp(O) → σ*C1'N9 interaction energy is similar to these bonds in the remote part of the proton donor. The above the trend in the N-glycosidic bond length (a > b > c). This is mentioned sum is higher and the length of N-glycosidic bond similar to the result obtained for the conformations of the ive is shorter in the syn conformations relative to the anti because model 3MDA. The lp(O) → σ*C1'N9 interaction increases the of an extra intramolecular improper hydrogen bond in the occupation number of σ*C1'N9 that can affect the N-glycosidic former. The longest C1´-O4´ and C1´-C2´ bonds and the bond length. Furthermore, the conformational changes likely shortest N-glycosidic bond correspond to 1´a with H2´···N3 influence the N-glycosidic bond through the intramolecular ch and H3´···N3 improper H-bonds, while the reverse is true for interactions between base moiety and the O4´ atom. 2´a without any improper H-bond. Similarly, the C2´-H2" Though the N-glycosidic bond length increases on bond is shorter than 1.090 Å and the C1´-O4´ and C1´-C2´ replacing the OH and OCH3 groups by the H atom, identical bonds in 2´b are longer than 2´a; thus, a shorter glycosidic trends are observed for that before and after modeling. A Ar bond can be predicted for 2´b. comparison of geometrical parameters of each conformation in 3MDA with those optimized after replacing the OH and OCH3 3MDA Conformations with the H atom, which will be made below, will confirm the Energetic details for the 3MDA conformations are influence of intramolecular interactions on the N-glycosidic presented in Table 1. Herein, m2b is the most stable bond. conformer at all levels of theory with the exception of MP2/6- It can be observed from the AIM results that the H···H 311++G**. The highest change in the ∆E value by changing intramolecular interaction in m1´a is replaced by O5´···N9 the basis set from 6-311++G** to AUG-cc-pVDZ corresponds electrostatic interaction in m1a; The O5´ and N9 atoms to m2b (by 0.32 kcal mol-1). possess negative and positive charges, respectively. As Unlike the model 3MDA, no meaningful relationship is mentioned earlier, H···H intramolecular interactions are observed between the relative energies and sugar accompanied by the N-glycosidic bond elongation, so in the conformation in 3MDA because of new intramolecular absence of this interaction the N-glycosidic bond in m1a (by interactions that are observed in the presence of OH and OCH3 ≈0.002 Å) is shorter than m1´a. functional groups. In comparison with m1´b, an extra intramolecular 915 www.SID.ir Effects of Sugar Ring Puckering, Anti-Syn Interconversion and Intramolecular Interactions hydrogen bond is observed between O5´ and H32 in m1b that the basis set changes from 6-311++G** to AUG-cc-pVDZ. is accompanied by C3'-H32 contraction and N9-C4 elongation The maximum change is equal to 1.44 kcal mol-1 (∼22.7%) for (Table 2). The C3´-H32 contraction comes along with a 2a. The relative energy changes ∼23% as the method changes concomitant increase in C-H stretching vibrational frequency from B3LYP to MP2 for 2b, which is the greatest variation when compared with m1'b (18.17 cm-1). The N-glycosidic upon changing the method. The trend in the relative energies bond in m1b is shorter than that in m1´b (by ≈0.007 Å) that of conformers in DA is 1b > 1a > 2b > 2a that is different could be attributed to the interaction in question. from that in the model DA. The most stable conformation in Similarly, m1c possesses an extra intramolecular improper DA is 1b while in 3MDA is m2b. The conformational hydrogen bond between O5´ and H32 relative to m1´c. The difference in the most stable conformations of DA and 3MDA D C3-H32 contraction (by 0.001 Å), the blue shift of C3´-H32 can be one of the most important parameters in alkylated base stretching vibrational frequency (by 19.93 cm-1), and the N9- recognition by DNA repair enzymes. C4 elongation (by 0.002 Å) (in remote part of proton donor) The order of occupation number of σ*C1'N9 is 2a > 1a > 1b are observed in m1c relative to m1´c. The O5´ atom is proton acceptor and the nucleobase is proton donor. The N9-C4 elongation leads to the C1´-N9 contraction such that the latter bond in m1c becomes shorter than that in m1'c (by ≈0.002 Å). The C2´···H32 electrostatic interaction in m2´a is replaced SI > 2b that is similar to the order of E(2) for lp(O) → σ*C1'N9 interaction. The increase in the occupation number of σ*C1'N9 leads to the increase in the N-glycosidic bond length. This observation confirms that the O4´···nucleobase interaction, which depends on sugar conformation, can affect the N- of by the O5'···H6 interaction in m2a. The new interaction that glycosidic bond length. Other intramolecular interactions can leads to the C8-H6 elongation (by 0.005 Å) and a concomitant also affect the N-glycosidic bond length as already mentioned. decrease in C8-H6 stretching vibrational frequency (by 60.77 The comparison of each conformation in DA with that in cm-1) relative to m2´a is categorized as a regular hydrogen the model DA confirms our previous results. The H2´···N3 ive bond. The O5'···H6 hydrogen bond is accompanied by an improper hydrogen bond in 1´a is replaced by the H5'···N3 increase in the C8-N9 bond length (0.004 Å) that leads to the hydrogen bond in 1a. This hydrogen bond is accompanied by C1'-N9 bond contraction (0.007 Å) in m2a relative to m2´a. the elongation of O5´···H5´ bond and red shift in its stretching This explains why the N-glycosidic bond length in m2a is vibrational frequency (316.72 cm-1). Thus, in the absence of shorter than that in m2´a (by 0.007 Å). H2'···N3 improper hydrogen bond, the O4´-C1´ and C2´-C1´ ch The H···H interaction in m2´b is replaced by the O5´···H6 bonds become shorter and the N-glycosidic bond becomes and O5´···H2´ interactions in m2b. The C8-H6 elongation in longer (by ≈0.006 Å, in comparison with 1'a). m2b (by 0.003 Å in comparison with m2´a) confirms that the The H2´···N3 and H4´···N3 improper hydrogen bonds are O5´···H6 interaction is a regular hydrogen bond that is observed in the AIM results of 1´b, while the H2´···N3 and Ar accompanied with the N9-C8 elongation (0.003 Å) and a O5´···H2´ improper hydrogen bonds and the H5'···N3 concomitant decrease in the C8-H6 stretching vibrational conventional hydrogen bonds are observed in 1b. The changes frequency (by 44.31 cm-1). The O5´···H2´ interaction could be in the stretching frequencies of proton donors are evidences considered as an improper hydrogen bond that causes for these interactions (see Table 5). The C2´-H2´ bond in 1b is contraction in the C2´-H2´ bond (by 0.004 Å), blue shift longer than 1´b, whereas the O4´-C1´, C2´-C1´, and N- (11.27 cm-1) in the stretching vibrational frequency, and glycosidic bonds in 1b are shorter than 1'b (by ≈0.009 Å). The expansion in the O4´-C1´ and C2´-C1´ bonds relative to m2´b. special triangular interaction in 1b probably does not allow the The N-glycosidic bond length in m2b is shorter than m2´b (by N-glycosidic bond elongation (see Fig. 2). ≈0.020 Å) that can be accounted for by the absence of H···H The O5´···H6 interaction is observed in the AIM results of interaction and the presence of O5´···H6 and O5´···H2´ 2a that is accompanied by the C8-N9 elongation (0.002 Å); interactions. this interaction is not observed in 2´a. Although the H2´···N3 improper hydrogen bond cannot be seen in the AIM results of DA Conformations 2a, the contraction of C2´-H2´ (0.001 Å) and the elongation of As can be seen in Table 1, the energy values decrease as O4´-C1´ (0.014 Å) and C2´-C1´ (0.004 Å) are observed for 916 www.SID.ir Ebrahimi et al. from that in the model 3MDA. This can be used to evaluate the role of conformational changes in the alkylated base recognition by DNA repair enzymes. The N-glycosidic bond length in the syn conformations was shorter than anti for 3MDA, the model 3MDA, and the model DA. The conformational changes can influence that bond through interaction with the O4´ atom. The C-H⋅⋅⋅N and C-H⋅⋅⋅O intramolecular interactions were observed for different conformations where all the C-H···N interactions could be D categorized as the improper hydrogen bonds. The improper hydrogen bonds were accompanied with the enlargement of the other two bonds in the remote part of proton donor; the N- 1b Fig 2. The molecular graph of 1b obtained from AIM analysis SI glycosidic bond contraction was observed when the remote part included one of the C1´-O4´, C1´-C2´, N9-C8 or N9-C4 bonds. On the other hand, the H···H interactions lead to the elongation of N-glycosidic bond. of at the B3LYP/6-311++G** level of theory. REFERENCES that. In addition, an increase in the C2´-H2´ stretching [1] M.R. Stratton, P.J. Campbell, P.A. 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