Theoretical study of the interaction pattern and the binding affinity between procaine and DNA bases

The interacting patterns and mechanism of the binding affinity between the local anaesthetic procaine and four DNA bases (adenine, cytosine, guanine and thymine) in neutral form have been investigated in gas phase using the Austin Model l and density functional methods. The results show that the complexes are mainly stabilized by the H-bonding interactions. The bond critical point properties of the optimized complexes were analyzed by using the atoms in molecules theory with DFT method and the results show that the presence of the C?H···O or C?H···N hydrogen bonding. The natural bond orbital analysis was performed to quantitatively evaluate the hydrogen bonding interaction. The interacting energy shows that the binding of procaine with guanine is the most strong, whereas its binding to cytosine exhibits relatively weaker stability. The strength order of the relevant transferred charge between procaine and DNA base with natural population analysis are consist with the HOMO–LUMO gap results for each complex. And the order is accord with the relevant electrochemical experimental results.     

Intrinsic acidity and redox properties of the adenine radical cation

The intrinsic chemical properties of the gaseous adenine radical cation were examined by using dual cell Fourier transform ion cyclotron resonance mass spectrometry. The adiabatic recombination energy of the radical cation (ionization energy of neutral adenine) was found by bracketing experiments to be 8.55 ± 0.1 eV (at 298 K; earlier literature values range from 8.3 to 8.9 eV). Based on this value, the heat of formation (ΔH_f²⁹⁸) of the adenine radical cation is estimated to be 246 ± 3 kcal/mol. The acidity (ΔH_acid²⁹⁸) of the adenine radical cation was bracketed to be 221 ± 2 kcal/mol. These thermochemical values suggest that the adenine radical cation reacts with neutral guanine by electron abstraction or proton transfer, with neutral cytosine by proton transfer, and via neither pathway with neutral thymine, molecular water or a sugar moiety of DNA (modeled by tetrahydrofuran). Experimental examination of the gas-phase reactivity of the adenine radical cation revealed a slow deuterium atom abstraction from perdeuterated tetrahydrofuran. Hence, in the absence of a nearby guanine or cytosine, the adenine radical cation may be able to abstract a hydrogen atom from a sugar moiety of DNA.     

On the structure and desorption dynamics of DNA bases adsorbed on gold: a temperature-programmed study

The structure and desorption dynamics of mono- and multilayer samples of adenine, cytosine, guanine, and thymine on polycrystalline gold thin films are studied using temperature-programmed desorption-infrared reflection absorption spectroscopy (TPD-IRAS) and temperature-programmed desorption-mass spectroscopy (TPD-MS). It is shown that the pyrimidines, adenine and guanine, adsorb to gold in a complex manner and that both adhesive (adenine) and cohesive (guanine) interactions contribute the apparent binding energies to the substrate surface. Adenine displays at least two adsorption sites, including a high-energy site (210 degrees C, approximately 136 kJ/mol), wherein the molecule coordinates to the gold substrate via the NH2 group in an sp3-like, strongly perturbed, nonplanar configuration. The purines, cytosine and thymine, display a less complicated adsorption/desorption behavior. The desorption energy for cytosine (160 degrees C, approximately 122 kJ/mol) is similar to those obtained for adenine and guanine, but desorption occurs from a single site of dispersed, nonaggregated cytosine. Thymine desorbs also from a single site but at a significantly lower energy (100 degrees C, approximately 104 kJ/mol). Infrared data reveal that the monolayer architectures discussed herein are structurally very different from those observed for the bases in the bulk crystalline state. It is also evident that both pyrimidines and purines adsorb on gold with the plane of the molecule in a nonparallel orientation with respect to the substrate surface. The results of this work are discussed in the context of improving the understanding of the design of capturing oligonucleotides or DNA strands for bioanalytical applications, in particular, for gold nanoparticle-based assays.     

At nonzero temperatures, stacked structures of methylated nucleic acid base pairs and microhydrated nonmethylated nucleic acid base pairs are favored over planar hydrogen-bonded structures: a molecular dynamics simulations study

The dynamic structure of all ten possible nucleic acid (NA) base pairs and methylated NA base pairs hydrated by a small number of water molecules (from 1 to 16) was determined by using molecular dynamics simulations in the NVE microcanonical and NVT canonical ensembles with the Cornell force field (W. D. Cornell, P. Cieplak, C. I. Bayly, I. R. Gould, K. M. Merz, D. M. Ferguson, D. C. Spellmeyer, T. Fox, J. E. Caldwell, P. Kollman, J. Am. Chem. Soc. 1995, 117, 5179). The presence of one water molecule does not affect the structure of any hydrogen-bonded (H-bonded) nonmethylated base pair. An equal population of H-bonded and stacked structures of adenine...adenine, adenine...guanine and adenine... thymine pairs is reached if as few as two water molecules are present, while obtaining equal populations of these structures in the case of adenine...cytosine, cytosine...thymine, guanine... guanine and guanine...thymine required the presence of four water molecules, and in the case of guanine...cytosine, six. A comparable population of planar, H-bonded and stacked structures for cytosine...cytosine and thymine... thymine base pairs was only obtained if at least eight water molecules hydrated a pair. Methylation of bases changed the situation dramatically and stacked structures were favoured over H-bonded ones even in the absence of water molecules in most cases. Only in the case of methyl cytosine...methyl cytosine, methyl guanine...methyl guanine and methyl guanine...methyl cytosine pairs were two, two or six water molecules, respectively, needed in order to obtain a comparable population of planar, H-bonded and stacked structures. We believe that these results give clear evidence that the preferred stacked structure of NA base pairs in the microhydrated environment, and also apparently in a regular solvent, is due to the hydrophilic interaction of a small number of water molecules. In the case of methylated bases, it is also due to the fact that the hydrogen atoms most suitable for the formation of H-bonds have been replaced by a methyl group. A preferred stacked structure is, thus, not due to a hydrophobic interaction between a large bulk of water molecules and the base pair, as believed.     

Theoretical determination of electron affinity and ionization potential of DNA and RNA bases

The ionization potentials and electron affinities of thymine, cytosine, adenine, guanine, and uracil were determined at density functional level using different exchange‐correlation functionals and basis sets. Results showed that the computed ionization potentials are very close to the experimental counterparts. The sign of adiabatic electron affinities of adenine, thymine, and uracil is unaffected by the used level of theory while that for guanine and cytosine depends on both the used potential and basis set. Vertical electron affinities are always negative in agreement with the experimental indications. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 1243–1250, 2000     

Selective determination of guanine and its nucleosides and nucleotides by reaction with phenylglyoxal as a fluorogenic reagent

A fluorimetric method is described for determining guanine in its nucleosides and nucleotides. The method is based on the reaction of the compounds with phenylglyoxal as a fluorogenic reagent in a weakly acidic solution (pH 4.0). The fluorescences produced show excitation and emission maxima around 365 and 510 nm, respectively. The conditions established for the reaction do not produce fluorescence from other nucleic acid bases such as adenine, cytosine, uracil and thymine, and their nucleosides and nucleotides. The method is sensitive and selective for guanine and its derivatives, with a detection limit of 47–310 pmol ml^?1 in the reaction mixture.     

Simple route to ferrocenylalkyl nucleobases. Antitumor activity in vivo

Ferrocenylalkyl nucleobases ( 1 – 14 ) were prepared via the reaction of the α‐(hydroxy)alkyl ferrocenes FcCHR(OH) (Fc = ferrocenyl; R = H, Me, Et, Ph) with thymine, cytosine, iodo‐cytosine and adenine in DMSO at 100 °C, yields being 50–80%. The antitumor activities of ferrocenylmethyl thymine ( 1 ) against solid tumor models, carcinoma 755 (Ca755) and Lewis lung carcinoma (LLC) were studied in vivo. Therapeutic synergism of antitumor activity against LLC was demonstrated in the case of combined application of compound 1 with anticancer drug cyclophosphamide. Copyright © 2009 John Wiley & Sons, Ltd.     

Separation of Nucleobases Using High‐performance Liquid Chromatography Coupled with Voltammetric Scanning

In this paper, a method based on chromatographic separation of analytes and their quantification using on‐line cyclic voltammetry is reported. The method based on high performance liquid chromatography on reverse phase column was optimized using free nucleobases‐guanine, adenine, thymine, and cytosine. The optimal separation of nucleobases was detected when using 0.05 M borate buffer (pH 9.0) as the mobile phase, at isocratic flow rate 1 mL min⁻¹, and at separation column temperature of 30 °C. The accurate timing of the cyclic voltammetry enabled us to quantify the concentrations of individual nucleobases by oxidation on glassy carbon electrode.     

Nanoswitches based on DNA base pairs: why adenine-thymine is less suitable than guanine-cytosine.

Substituted Watson–Crick guanine–cytosine (GC) base pairs were recently shown to yield robust three‐state nanoswitches. Here, we address the question: Can such supramolecular switches also be based on Watson–Crick adenine‐thymine (AT) base pairs? We have theoretically analyzed AT pairs in which purine‐C8 and/or pyrimidine‐C6 positions carry a substituent X=NH^?, NH₂, NH₃⁺ (N series), O^?, OH or OH₂⁺ (O series), using the generalized gradient approximation (GGA) of density functional theory at the BP86/TZ2P level. Thus, we explore the trend in geometrical shape and hydrogen bond strengths in AT pairs along a series of stepwise protonations of the substituents. Introducing a charge on the substituents leads to substantial and characteristic changes in the individual hydrogen bond lengths when compared to the neutral AT pair. However, the trends along the series of negative, neutral, and positive substituents are less systematic and less pronounced than for GC. In certain instances, internal proton transfer from thymine to adenine occurs. Our results suggest that AT is a less suitable candidate than GC in the quest for chemically controlled nanoswitches.     

The self-consistent-field method in the semiempirical approximation for states with unclosed shells for nucleic acid bases

The ionized and triplet -electron states are derived. The order of increasing ionization potential is found to be quanine, cytosine, adenine, uracil, thymine, while the order in electron affinity is adenine, guanine, thymine, uracil, cytosine. It is found that the energies of the lowest triplet states are considerably reduced by reminimization of the wave functions, the reduction for adenine being almost 20% of the transition energy. Nearly equal values are obtained for the energies of transition to the lowest triplet states as found by the method of unclosed shells and by the method of interaction of singly excited configurations.     

Intrinsic lifetimes of the excited state of DNA and RNA bases

The lifetimes of the excited state of free nucleobases were measured in the gas phase for the first time. They are, respectively, 1.0 and 0.8 ps for the purine bases adenine (shown above) and guanine and 3.2, 2.4, and 6.4 ps for the pyrimidine bases cytosine, uracil, and thymine at 267 nm. The longer lifetimes of the pyrimidine bases may be associated with their higher propensity toward photodegradation, especially in the case of thymine. The ultrashort lifetime of nucleobases conventionally known in solution was found to be an intrinsic molecular property due to extremely facile internal conversion, and therefore the lifetime should be largely independent of the medium at this energy, that is, whether in vacuo, in solution, or in vivo. The evolutionary selection of nucleobases as the durable carriers of genetic information is suggested to be due to their inherent immunity from photochemical reactions.     

Na+, Mg2+, and Zn2+ binding to all tautomers of adenine, cytosine, and thymine and the eight most stable keto/enol tautomers of guanine: a correlated ab initio quantum chemical study

Interactions of adenine, cytosine, guanine, and thymine with Na(+), Mg(2+), and Zn(2+) cations were studied using an approximate resolution of identity correlated second-order MP2 (RI-MP2) method with the TZVPP ([5s3p2d1f/3s2p1d]) basis set. All existing tautomers of adenine, cytosine, and thymine and the eight most stable keto/enol tautomers of guanine were considered. Cations bind mostly in a bidentate manner, and stabilization energies of these complexes are larger than those in the case when cations bind in a unidentate manner. The cation...Y (Y equal to N or O) distances for divalent metals are shorter than those for Na(+) and for Zn(2+) are mostly shorter than the Mg(2+)...Y distance. The intermolecular distances between the cation and the base for complexes containing adenine and cytosine are systematically shorter than those for complexes containing guanine and thymine. Only for cytosine the canonical keto/amino tautomer structure with ions represents the global minimum. For guanine, the metalated canonical form is again the most stable, but its stabilization energy is within less than 5% of the stabilization energies of the two other rare tautomers, which indicates that the canonical form and these two rare tautomers could coexist. The canonical structures of adenine and thymine in the presence of ions are considerably less stable (by more than 10%) than the complexes of the rare tautomers. It can be concluded that the interaction of Na(+), Mg(2+), and Zn(2+) cations with cytosine in the gas phase will not induce the change of the canonical form to the rare tautomeric form. In the case of isolated guanine, the equilibrium of the canonical form with rare tautomers can be found. For isolated adenine and thymine the presence of rare tautomers is highly probable.     

Structural and electronic property changes of the nucleic acid bases upon base pair formation

A systematic study of structures and electronic properties has been carried out for the nucleic acid bases adenine, guanine, thymine, and cytosine and for the base pairs adenine–thymine and guanine–cytosine. We focus our attention on these properties, which experience significant changes when single nucleic bases join to form base pairs. Such properties are expected to play an important role during the formation of the DNA molecule in its B conformation. All-electron calculations with inclusion of correlation effects were performed according to the local and nonlocal density functional approaches. We compare our results with previous ab initio and semiempirical values and with available experimental data. Advantages and disadvantages for these density functional-based methods are discussed. We conclude that applications of such models to investigate larger compounds of a similar nature are promising. © 1994 by John Wiley & Sons, Inc.     

Stacking of the mutagenic DNA base analog 5-bromouracil

The potential energy surface of the stacked 5-bromouracil/uracil (BrU/U) dimer has been investigated in the gas phase and in solution (water and 1,4-dioxane), modeled by a continuum solvent using the polarizable continuum model. Minima and transition states were optimized using DFT (the M06-2X density functional and the 6-31+G(d) basis set). Six stacked gas-phase BrU/U minima were located: four in the face-to-back orientation and two face-to-face. The global minimum in the gas phase is a face-to-face structure with a twist angle of 60° and a zero-point energy-corrected interaction energy of ?10.7 kcal/mol. The BrU/U potential energy surface is geometrically and energetically similar to that of U/U (Hunter and Van Mourik in J Comput Chem 33:2161, 2012). Energy calculations were also performed on experimental geometries of stacked dimers (47 containing BrU stacking with either adenine, cytosine, guanine or thymine and 51 containing thymine also stacking with one of those four bases) taken from DNA structures in the Protein Data Bank. Single-point interaction energies were computed at different levels of theory including MP2, CCSD(T) and DFT using the mPW2PLYP-D double-hybrid functional augmented with an empirical dispersion term, using basis sets ranging from aug-cc-pVDZ to aug-cc-pVQZ. No strong evidence was found for the suggestion that the mutagenicity of BrU is due to enhanced stacking of BrU compared to the corresponding stacked dimers involving thymine.     

Fluorescence and electrochemical detection of pyrimidine/purine transversion by a ferrocenyl aminonaphthyridine derivative

A novel hydrogen bond-forming ligand for pyrimidine/purine transversion, which contains both a fluorescent naphthyridine moiety and a ferrocenyl group as an electrochemical indicator, is described. Hydrogen bond-mediated recognition for a target nucleobase at an abasic site in a DNA duplex is confirmed by both fluorescence and electrochemical measurements. The analysis by fluorescence titration reveals that the ligand shows significant fluorescent quenching upon formation of a 1 : 1 complex with the target nucleobase opposite the abasic site, and the selectivity is in the order of cytosine > thymine > adenine, guanine, reflecting the stability of the hydrogen bond formation.     

Preparation and antiviral properties of new acyclic, achiral nucleoside analogues: 1- or 9-[3-hydroxy-2-(hydroxymethyl)prop-1-enyl]nucleobases and 1- or 9-[2,3-dihydroxy-2-(hydroxymethyl)propyl]nucleobases

Acyclic, achiral nucleoside derivatives 1b-e of adenine, cytosine, 5-methylcytosine, and guanine, containing a 3-hydroxy-2-(hydroxymethyl)prop-1-enyl group on N-1 or N-9, have been prepared analogously to the previously described thymine derivative 1a. In contrast to the adenine and guanine derivatives, the cytosine derivative 9 was unstable, and was obtained in a low yield due to side reactions. These include cleavage of the propenyl group from the base, and the formation of a bicyclic compound. The thymine derivative, although stable under neutral conditions, likewise underwent a reversible cyclization reaction (Michael addition) in the presence of acids or bases. The 5-methylcytosine derivative was stable under neutral and basic conditions. Four other nucleoside derivatives 26a-d containing a 2,3-dihydroxy-2-(hydroxymethyl)propyl group on N-1 or N-9, three of which are new, have likewise been prepared. All compounds were evaluated as antiviral agents against HIV-1 and HSV-1 but were devoid of antiviral activity.     

Natural resonance structures and aromaticity of the nucleobases

Natural resonance theory (NRT) and nucleus- independent chemical shift (NICS) analyses have been applied to the standard nucleobases adenine, guanine, cytosine, uracil, and thymine. The molecular electron densities were obtained from density functional theory calculations at the B3LYP level and ab initio calculations at the HF, MP2, and CCD levels. Compared with the dominance of the two Kekulé structures in benzene, the structural modifications in the forms of endocyclic heteroatoms and exocyclic substituents introduce various degrees of charge separation in nucleobases. As a result, the leading resonance structures for cytosine, uracil, and thymine are found to be covalent structures, but their weightings decrease to ~30% in the NRT expansion. For adenine and guanine, the covalent structures have weightings of ~20%, and the leading ionic resonance structures have weightings of as high as about 8%. Methods that include electron correlation effects, B3LYP, MP2, and CCD, give smaller weightings for the covalent structures than HF. However, MP2 and CCD results often include “strange” resonance structures with connections between unbonded vicinal atoms, making DFT at the B3LYP level the better choice for calculating these molecules’ electron density. The NICS at the ring center shows that the six-membered rings in cytosine, uracil, thymine, and guanine are nonaromatic with NICS within − 3 to − 1 ppm, while it is − 7.3 ppm for the six-membered ring in adenine. The NICS of the five-membered rings of adenine and guanine is around − 12 ppm, a slight decrease from the value of − 15.0 ppm for pyrrole.     

In vitro nonenzymatic glycation of DNA nucleobases: an evaluation of advanced glycation end products under alkaline pH

The advanced glycation end products (AGEs) of DNA nucleobases have received little attention, perhaps due to the fact that adenine, guanine, cytosine and thymine do not dissolve under mild pH conditions. To maintain nucleobases in solution, alkaline pH conditions are typically required. The objectives of this investigation were twofold: to study the susceptibility of DNA nucleobases to nonenzymatic attack by different sugars, and to evaluate the factors that influence the formation of nucleobase AGEs at pH 12, i.e., in an alkaline environment that promotes the aldo–keto isomerization and epimerization of sugars. Varying concentrations of adenine, guanine, thymine and cytosine were incubated over time with constant concentrations of D-glucose, D-galactose or D/L-glyceraldehyde under different conditions of temperature and ionic strength. Incubation of the nucleobases with the sugars resulted in a heterogeneous assembly of AGEs whose formation was monitored by UV/fluorescence spectroscopy. Capillary electrophoresis and HPLC were used to resolve the AGEs of the DNA adducts and provided a powerful tool for following the extent of glycation in each of the DNA nucleobases. Mass spectrometry studies of DNA adducts of guanine established that glycation at pH 12 proceeded through an Amadori intermediate.     

Calibration and applications of the ΔMP2 method for calculating core electron binding energies

We calibrated a method for the evaluation of core electron binding energies, based on the energy differences between the cation and neutral molecule evaluated at the level of M?ller-Plesset perturbation theory. The central feature of the method is the use of a mixed basis set: a large all-electron basis set is used for the atom whose core electron is removed, while the model core potential basis set is employed for all remaining atoms. Calibration was carried out for 55 molecules and 114 binding energies of 1s core electrons for the atoms C, N, O, and F. The average absolute deviation for all the core electron binding energies is 0.163 eV. The method was applied to the calculation of the core electron binding energies of five nucleic acid bases (uracil, adenine, cytosine, guanine, and thymine) and several of their low-energy tautomers.     

Activation barriers for DNA alkylation by carcinogenic methane diazonium ions

Methylation reactions of the DNA bases with the methane diazonium ion, which is the reactive intermediate formed from several carcinogenic methylating agents, were examined. The SN2 transition states of the methylation reactions at N7, N3, and O6 of guanine; N7, N3, and N1 of adenine; N3 and O2 of cytosine; and O2 and O4 of thymine were calculated using the B3LYP density functional method. Solvation effects were examined using the conductor-like polarizable continuum method and the combined discrete/SCRF method. The transition states for reactions at guanine N3, adenine N7, and adenine N1 are influenced by steric interactions between the methane diazonium ion and exocyclic amino groups. Both in the gas phase and in aqueous solution, the methylation reactions at N atoms have transition states that are looser, and generally occur earlier along the reaction pathways than reactions at O atoms. The forming bonds in the transition states in water are 0.03 to 0.13 A shorter than those observed in the gas phase, and the activation energies are 13 to 35 kcal/mol higher. The combined discrete/SCRF solvation energy calculations using base-water complexes with three water molecules yield base solvation energies that are larger than those obtained from the CPCM continuum method, especially for cytosine. Reactivities calculated using barriers obtained with the discrete/SCRF method are consistent with the experimentally observed high reactivity at N7 of guanine.