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In the present density functional theory study, we have compared intrinsic properties of non-natural nucleobases ( acA, acG, acC, and acT nucleobases) such as proton affinities, gas phase acidities, tautomerization, and hydrogen-bonding properties with those in normal Watson-Crick nucleobases (A, G, C, T nucleobases). The hydrogen-bonding interactions in non-natural and Watson-Crick base pairs were studied at B3LYP/6-311++G (d,p) level regarding their geometries, energies, and topological features of the electron density. The quantum theory of atoms-in-molecule (QTAIM) and natural bond orbital (NBO) analyses were employed to elucidate the interaction characteristics in base pairs. The electron density ρ( r) as well as its Laplacian $$ \nabla^{2} $$ ρ( r) at the hydrogen bond critical point predicted by QTAIM is strongly correlated with hydrogen bond structural parameter and the second-order perturbation energies in NBO scheme. Our results show that most of hydrogen bonds in normal Watson-Crick and non-natural base pairs must be considered as electrostatic interactions. Results of calculations revealed that energetic values of hydrogen bonds in T- A base pair are more than those in ac T- ac A base pair, while values of hydrogen bonds in C- G base pair and ac C- ac G base pair are almost the same. These results confirmed stability order of stabilization energies of these base pairs. [ABSTRACT FROM AUTHOR]

Glutathione tripeptide (γ-glutamyl-cysteinyl-glycine) is a flexible molecule and its conformational energy landscape is strongly influenced by forming intramolecular hydrogen bond, its charge and the environment. This study employs DFT-B3LYP method with the 6-31+G (d,p) basis set to carry out conformational analysis of neutral, zwitterionic, cationic, and anionic forms of glutathione. In analyzing the structural characteristics of these structures, intramolecular hydrogen bonds were identified and characterized in details by topological parameters such as electron density ρ( r) and Laplacian of electron density $$ \nabla^{2} $$ρ( r) from Bader's atom in molecules theory. Charge transfer energies based on natural bond orbital analysis are also considered to interpret these intramolecular hydrogen bonds. Our results show that these hydrogen bonds are partially electrostatic and partially covalent in nature, in which the covalent contribution increases as the stabilization energy of hydrogen bond increases. Furthermore, the back bone and side chain (Ramachandran map) orientations of various ionic forms of glutathione have been studied and conformation of each constitution of glutathione tripeptide (i.e., Glu, Cys, and Gly moieties) was determined. In most species side chain conformation were found to be hindered gauche-gauche orientation by intramolecular hydrogen bonds. [ABSTRACT FROM AUTHOR]

Thiotepa ( N,N′, N″-triethylenethiophosphoramide) and its major metabolite (Tepa) as trifunctional alkylating agents has recently been used in cancer therapy. In vivo and vitro studies show the possible pathways of alkylation of DNA by Thiotepa and Tepa. Two pathways are suggested, but the main pathway of mechanism remains unclear. In pathway 1, forming cross-links with DNA molecules can be carried out via two different mechanisms. In first mechanism, these agents undergo the ring opening reaction which is initiated by protonating aziridine, which then becomes the main target of nucleophilic attack by the N7-Guanine of DNA. The second probable mechanism is ring opening of aziridyl group by nucleophilic attack of N7-Guanine without initial protonation. Thiotepa and Tepa in pathway 2, act as a cell penetrating carrier for aziridine, which is released via hydrolysis. The released aziridine can form a cross-link with N7-Guanine. In this study, we calculated the activation free energy and kinetic rate constant for alkylating the Guanine via the first pathway to determine the most precise mechanism by applying density functional theory using B3LYP method. We carried out geometrical optimizations with the conductor-like polarizable continuum model to account for the solvent effect, and the results were compared with those in the gas phase. Hyperconjugation stabilization factors that affect on stability of generated transition state were investigated by natural bond order analysis. Furthermore, quantum theory of atoms in molecules analysis was performed to extract the bond critical points properties because the electron densities can be considered as a good description of the strength of different types of interactions. [ABSTRACT FROM AUTHOR]

Etheno-damaged DNA adducts such as 3, N-ethenocytosine, N,3-ethenoguanine, and 1, N-ethenoguanine are associated with carcinogenesis and cell death. These inevitable damages are counteracted by glycosylase enzymes, which cleave damaged nucleobases from DNA. Escherichia coli alkyl purine DNA glycosylase is the enzyme responsible for excising damaged etheno adducts from DNA in humans. In an effort to understand the intrinsic properties of these molecules, we examined gas-phase acidity values and proton affinities (PA) of multiple sites of these molecules as well as equilibrium tautomerization and base pairing properties by quantum mechanical calculations. We also used calculations to compare the acidic and basic properties of these etheno adduct with those of the normal bases-cytosine and guanine nucleobases. We hypothesize that alkyl DNA glycosylase may cleave certain damaged nucleobases as anions and that the active site may take advantage of a nonpolar environment to favor deprotonated cytosine or guanine as a leaving group versus damaged nucleobases. [ABSTRACT FROM AUTHOR]

The relative stabilities and noncovalent interactions of the six low-lying energy tautomers of cytosine nucleobase with some biological anions (such as F, Cl, and CN) have been investigated in gas phase by density functional theory (DFT) method in conjunction with 6-311++G (d,p) atomic basis set. Furthermore, to systematically investigate all possible tautomerisms from cytosine induced by proton transfer, we describe a study of structural tautomer interconversion in the gas phase and in a continuum solvent using DFT calculation. We carried out geometrical optimizations with the integral equation formalism of polarizable continuum (IEF-PCM) model to account for the solvent effect, and the results were compared with those in the gas phase. The result of calculation revealed that anions bind mostly in a bidentate manner via hydrogen bond, and stabilization energies of these complexes are larger than those in the case when anions bind in a monodentate manner. The quantum theory of atoms in molecules (QTAIM), natural bonding orbital (NBO) and energy decomposition analysis (EDA) have also been applied to understand the nature of hydrogen bond interactions in these complexes. NBO analysis reveals that the interaction patterns between the anions and the tautomers are σ-type interaction between lone pairs and $$ \sigma_{{_{{{\text{N}}--{\text{H}}}} }}^{*} $$, $$ \sigma_{{_{{{\text{O}}--{\text{H}}}} }}^{*} $$ and $$ \sigma_{{_{{{\text{H}}--{\text{F}}}} }}^{*} $$ antibonding orbitals. Also, according to these theories, the interactions are found to be partially electrostatic and partially covalent. EDA results identify that these bonds have less than 35% covalent character and more than 65% electrostatic, and the covalent character increases in different anions in the order F > CN > Cl. On the other hand, orbital interaction energies of complexes of F anion are more than those of Cl and CN complexes. The lower orbital interaction energies in complexes of Cl and CNanions imply less charge transfer and stronger ionic bond character. Furthermore, relationship between the orbital interaction energy ( E) with hydrogen bonding energy ( E) and the electron density (ρ( r)) with hydrogen bonding energy of F, Cl and CN complexes have also been investigated. [ABSTRACT FROM AUTHOR]

The cation radicals of DNA constituents generated by the ionizing radiation initiate the alteration of the bases, which is one main type of cytotoxic DNA lesions. These cation radical spices are known for their role in producing nucleic acid strand break, and it is important to identify the cation radical formation at particular atomic site in these molecules so that the major pathway for the nucleic acid damage may be trapped. In the present study, we explored theoretically energetic, structural, and electronic properties of the possible radicals formed via proton atom abstraction at various sites of sugar part of deoxycytidine cation radical by employing density functional theory at B3LYP/6-311++G (d,p) level. The computation revealed 0.0-22.6 kcal/mol energy disparity in these radicals. Radical-centered carbon increases the extent of bonding with its adjacent atoms. This tendency should be important in predicting the reactivity of sugar-based radicals. Based on DFT calculations, sugar radicals of deoxycytidine have following stability order: raH1′ > raH2′ > raH4′ > raH3′ > raH5′ > raO5′H > raO3′H. Furthermore, influence of cation radical formation on acidities of multiple sites in deoxycytidine nucleosides was investigated. For instance upon cation radical formation, ΔH of O3′H and O5′H sites of deoxycytidine varies from 348.6 and 351.5 to 228.8 and 227.5 kcal/mol, respectively. [ABSTRACT FROM AUTHOR]

Influence of the addition of water molecules ( n = 1-6) on the interaction energy between Li, Na, K cations and indole molecule as tryptophan amino acid residue is considered at MP2(FULL)/6-311++G(d,p)//B3LYP/6-311++G(d,p) levels of theory. The calculations suggest that the size of cation and the number of water molecules are two important factors that affect the interaction energy between the hydrated metal cation and indole molecule. The strength of cation-π interactions get substantially reduced when the metal ion is solvated or the size of metal cation increases. Quantum theory of atoms in molecules analysis of cation-π interaction indicates that there is a correlation between the electron density (ρ( r)) in the cage critical points generated upon complexation and the distance between metal cation and centroid of phenyl ring in indole molecule. [ABSTRACT FROM AUTHOR]

The B3LYP/6-311++G (d,p) density functional approach was used to study the gas-phase metal affinities of Guanosine (ribonucleoside) for the Li, Na, K, Mg, Ca, Zn, and Cu cations. In this study we determine coordination geometries, binding strength, absolute metal ion affinities, and free energies for the most stable products. We have also compared the results for Guanosine, with our previously reported results for 2′-Deoxyguanosine. Based on the results, it is obvious that MIA is strongly dependent on the charge-to-size ratio of the cation. Guanosine interacts more strongly with Zn than do with Mg, Ca, and Cu and therefore stronger interactions lead to higher MIA. In both free molecules and their complexes, the Syn orientation of the base is stabilized by an intramolecular O5′-H···N3 hydrogen bond and the anti orientation of the base is stabilized by an intramolecular C-H···O hydrogen bond formed between the (C8-H8) and the O5′ atom of the sugar moiety. It is also interesting to mention that linear correlation between calculated MIA values and the atomic numbers ( Z) of the metal ions of Li, Na, and K were found. Furthermore, the influences of metal cationization on the strength of the N-glycosidic bond, torsion angles, angle of pseudorotation ( P), and intramolecular C-H···O and O-H···O hydrogen bonds have been studied. Natural bond orbital (NBO) analysis was performed to calculate the charge transfer and natural population analysis of the complexes. Quantum theory of atoms in molecules (QTAIM) was also applied to determine the nature of interactions. [ABSTRACT FROM AUTHOR]

Hydrogen bonding interactions between thymine nucleobase and 2′-deoxythymidine nucleoside (dT) with some biological anions such as F (fluoride), Cl (chloride), OH (hydroxide), and NO (nitrate) have been explored theoretically. In this study, complexes have been studied by density functional theory (B3LYP method and 6-311++G (d,p) basis set). The relevant geometries, energies, and characteristics of hydrogen bonds (H-bonds) have been systematically investigated. There is a correlation between interaction energy and proton affinity for complexes of thymine nucleobase. The nature of all the interactions has been analyzed by means of the natural bonding orbital (NBO) and quantum theory atoms in molecules (QTAIM) approaches. Donors, acceptors, and orbital interaction energies were also calculated for the hydrogen bonds. Excellent correlations between structural parameter (δ R) and electron density topological parameter ( ρ) as well as between E(2) and ρ have been found. It is interesting that hydrogen bonds with anions can affect the geometry of thymine and 2′-deoxythymidine molecules. For example, these interactions can change the bond lengths in thymine nucleobase, the orientation of base unit with respect to sugar ring, the furanose ring puckering, and the C1′-N1 glycosidic linkage in dT nucleoside. Thus, it is necessary to obtain a fundamental understanding of chemical behavior of nucleobases and nucleosides in presence of anions. [ABSTRACT FROM AUTHOR]