Comprehensive study of the effects of methylation on tautomeric equilibria of nucleic acid bases

Minor tautomers of nucleic acid bases can result by intramolecular proton transfer. These rare tautomers could be stabilized through the addition of methyl groups to DNA bases. A comprehensive theoretical study of tautomers of methylated derivatives of guanine, adenine, cytosine, thymine, and uracil was performed. Molecular geometries of all tautomers were obtained at the density functional theory and MP2 levels with the 6-31G(d,p) basis set, and single-point calculations were performed at the CCSD(T)/6-311G(d,p) level. Tautomers obtained by protonation at the preferred protonation site for methylated isolated bases were compared to their nonmethylated counterparts. The effects of methylation on the relative stabilities of nucleic acid base tautomers are also studied and discussed in this work. The results suggest that some sites on the bases may not be mutagenic and may even stabilize the canonical Watson-Crick form. The results also indicate that a number of methylation sites can stabilize the tautomers, suggesting possible mechanisms for mutagenic changes.     

Theoretical study of tautomeric and ionizing effects of guanine,cytosine, and their methyl derivatives

The study of pre-translational effects (ionization, tautomerization) and post-translational effects (methylation) of guanine and cytosine has only recently been the focus of some studies. These effects can potentially help regulate gene expression as well as potentially disrupt normal gene function. Because of this wide array of roles, greater insight into these effects in deoxyribonucleic acids (DNA) are paramount. There has been considerable research of each phenomenon (tautomerization, methylation and ionization) individually. In this work, we attempt to shed light upon the pre- and post-translational effects of guanine and cytosine by investigating the electron affinities (EAs) and ionization potentials (IPs) of the major and minor tautomers and their methyl derivatives. We performed all calculations using the density functional theory B3LYP functional accompanied with 6-311G (d,p), 6-311+G (d,p), and 6-311++G (df,pd) basis sets. Our results reveal that the cytosine tautomer has a higher EA and IP than the guanine tautomers. The higher EA suggest that an electron that attaches to the GC base pair would predominately attach to the cytosine instead of guanine. The higher IP would suggest that an electron that is removed from the GC base pair would be predominately removed from the guanine within the base pair. Understanding how tautomerization, ionization, and methylation differences change effects, discourages, or promotes one another is lacking. In this work, we begin the steps of integrating these effects with one another, to gain a greater understanding of molecular changes in DNA bases.     

A DFT study of solvation effects on the tautomeric equilibrium and catalytic ylide generation of thiamin models

Thiamin diphosphate (ThDP) is the biologically active form of vitamin B1 and an essential cofactor for a number of enzymes. The effect of solvent polarity on the tautomeric equilibria of ThDP using three model systems of the 4'-aminopyrimidine ring is studied by density functional theory calculations (B3LYP/6-311+G(d,p)//B3LYP/6-31G(d)) in the gas phase and selected solvents (cyclohexane, ether, dichloroethane, and water). Solvation effects are investigated using three different schemes: implicit solvation by a continuum model, explicit solvation by inclusion of three water molecules mimicking the first solvation shell of the enzymatic environment, and by a mixed implicit/explicit solvation model. The 4'-aminopyrimidine tautomer is more stable than the 1',4'-iminopyrimidine tautomer in all solvation schemes employed; however, the trend for the stabilities of the 1',4'-iminopyrimidine tautomer in the solvents depends on the specific ThDP-model. Formation of the catalytic important ylide for ThDP-dependent enzymes by deprotonation of ThDP(C2) is also investigated by localization of transition states for two possible pathways. Only the less stable tautomer, 1',4'-iminopyrimidine ThDP, is able to form the catalytic active ylide. Generation of the ylide through a direct intramolecular proton transfer from ThDP(C2) to the ThDP(N4') nitrogen lone pair is favored by 6 kcal/mol in the gas phase, as compared to a water-mediated ylide generation. However, inclusion of a dielectric medium reduces this difference dramatically. Furthermore, inclusion of two water molecules to model the apoenzymatic environment lowers the activation energies of both direct and water-mediated ylide generation.     

Influence of excitation and solvation on the shift of tautomeric equilibrium. A quantum-mechanical study

Two quantum-mechanical models are proposed to described a shift of tautomeric equilibrium as a result of electronic excitation and change of environment. According to the first n PD MEP model which is used to estimate the relative solvation effect on the stability of tautomers in an excited state, the calculation of the interaction energy between a solvent (simulated by a set of n point dipoles, n PD) and an excited solute molecule is based on the molecular electrostatic potential (MEP) of the corresponding excited state. In the second n PDQ model, a solvent represented by a set of n point dipoles and quadrupoles (n PDQ) modifies the solute's hamiltonian via an electrostatic interaction contribution. Comparing the results of the calculation for isolated and solvated tautomers, the n PDQ model is used to estimate the influence of electronic excitation on the change of relative stability of tautomers existing in a solution. An application of both models to 2- and 4-oxopyridine predicts a shift of the tautomeric equilibria in their excited states in accordance with experimental evidence.     

Effect of water on the tautomeric equilibrium of uracil monoanions. A PCILO study

The PCILO method is used to calculate the stabilization energies of the anionic forms of uracil by water molecules forming the first hydration shell of the tautomers. The results show that the 1-HU^– tautomer is more stabilized by the solvent effect than the 3-HU^– tautomer by about 8 kcal/mole. The effect brings closer together the energies of the two tautomers which differ intrinsically by about 13 kcal/mole in favour of the 3-HU^– form. It operates in the direction inferred from experimental studies.This work was supported in part by R.C.P. 173 of the Centre National de la Recherche Scientifique of France and in part by the Polish Academy of Sciences within the project 09.3.1.     

Investigation of the tautomeric equilibrium of some phenylazonaphthols

The tautomeric equilibrium of phenylazonaphthols was investigated by the HMO method and by IR spectroscopy. It was found that in the case of 4-phenylazo-1-naphthol the thermodynamic stability of the tautomers was approximately the same, in the case of 1-phenylazo-2-naphthol the naphthoquinone hydrazone tautomer was substantially more stable.     

A photoelectron study (HeI,HeII) of the tautomeric equilibrium of chloro- and bromo-1,2,4-triazoles

Photoelectron spectroscopy HeI,HeII and quantum mechanical calculations (STO-3G) were used to analyze the electronic structure of tautomers of 1,2,4-triazole and its halogenated derivatives.The photoelectron spectra of the title compounds compared to those of fixed structure models demonstrated that 3-chloro and 5-bromo-1,2,4-(1H)-triazole exist in the vapor phase.     

Factors that affect the tautomeric equilibrium of hydroxyazopyridine derivatives

The ratio of azo and quinonehydrazone forms of 3-hydroxy-6-phenylazopyridine derivatives was determined by IR and electronic spectroscopy. The formation of two crystalline modifications of 2-methoxy-3-hydroxy-6-phenylazopyridine is explained by crystallization of the molecules either in the form of dimers of predominantly the quinonehydrazone form or in the form of polyassociates of the azo form, which are formed by a strong hydrogen bond.Communication VII from the series Structures and Properties of Dyes, See [1] for communication VI.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1364–1370, October, 1974.     

Mechanistic study on DNA mutation of the cytosine methylation reaction at C5 position

DNA methylation is a crucial epigenetic mark connected to conventionally changing the DNA bases, typically by adding methyl groups into DNA bases. Methylation of cytosine at the C5 position (5-methylcytosine) occurs mostly in the context of cytosine-phosphate-guanine dinucleotides, the methylation of which has important impacts on gene regulation and expression. However, the mechanistic details of this reaction are still debatable concerning the concertedness of the key reaction steps and the roles played by the base that abstracts the proton in the β-elimination and water molecules at the active site. To gain a deeper insight into the formation of 5-mehtylcytosine, an extensive density functional theory (DFT) study was performed with the B3LYP functional in conjunction with different basis sets. Our study has clearly established the mechanistic details of this methylation approach, based on which the roles of conserved active site residues, such as glutamic acid and waters, are well understood. Our results show that the reaction of 5-methylcytosine follows a concerted mechanism in which water molecules are critically involved. Moreover, arginine and alanine give more significant catalytic effects than glutamic acid on the 5-methylcytosine process. Considering the effect of Alanine, Arginine, and one water bridging molecule, the activation energy is 31 kJ mol^?1 calculated at B3LYP/6-31G(d) level of theory.     

Influence of intramolecular hydrogen bonds on the tautomeric equilibrium of 1,3-diketones

The paper deals with a quantitative characterization of the influence of multiple intramolecular hydrogen bonds on the tautomeric equilibrium of 1,3-diketones by means of NMR-spectroscopy. The contents of the keto- and two enol forms of 1-(o-hydroxyphenyl) -1,3-butandione and 1-(o-methoxyphenyl)-1,3-butandione in tetrachloromethane, deuterochloroforme, acetone-d₆ and acetonitrile-d₃ are compared.The intramolecular hydrogen bond between the phenolic hydroxyl group and the aromatic carbonyl group in 1-(o-hydroxyphenyl)-1,3-butandione shifts are keto-enol equilibrium toward the keto-tautomer and enol-enol equilibrium toward the tautomer with an enolized aliphatic carbonyl group.     

2-Pyridinethiol/2-pyridinethione tautomeric equilibrium. A comparative experimental and computational study

The gas phase and solvent dependent preference of the tautomerization between 2-pyridinethiol (2SH) and 2-pyridinethione (2S) has been assessed using variable temperature Fourier transform infrared (FTIR) experiments, as well as ab initio and density functional theory computations. No spectroscopic evidence (nu(S)(-)(H) stretch) for 2SH was observed in toluene, C(6)D(6), heptane, or methylene chloride solutions. Although, C(s)() 2SH is 2.61 kcal/mol more stable than C(s)() 2S (CCSD(T)/cc-pVTZ//B3LYP/6-311+G(3df,2p)+ZPE), cyclohexane solvent-field relative energies (IPCM-MP2/6-311+G(3df,2p)) favor 2S by 1.96 kcal/mol. This is in accord with the FTIR observations and in quantitative agreement with the -2.6 kcal/mol solution (toluene or C(6)D(6)) calorimetric enthalpy for the 2S/2SH tautomerization favoring the thione. As the intramolecular transition state for the 2S, 2SH tautomerization (2TS) lies 25 (CBS-Q) to 30 kcal/mol (CCSD/cc-pVTZ) higher in energy than either tautomer, tautomerization probably occurs in the hydrogen bonded dimer. The B3LYP/6-311+G(3df,2p) optimized C(2) 2SH dimer is 10.23 kcal/mol + ZPE higher in energy than the C(2)(h)() 2S dimer and is only 2.95 kcal/mol + ZPE lower in energy than the C(2) 2TS dimer transition state. Dimerization equilibrium measurements (FTIR, C(6)D(6)) over the temperature range 22-63 degrees C agree: K(eq)(298) = 165 +/- 40 M(-)(1), DeltaH = -7.0 +/- 0.7 kcal/mol, and DeltaS = -13.4 +/- 3.0 cal/(mol deg). The difference between experimental and B3LYP/6-311+G(3df,2p) [-34.62 cal/(mol deg)] entropy changes is due to solvent effects. The B3LYP/6-311+G(3df,2p) nucleus independent chemical shifts (NICS) are -8.8 and -3.5 ppm 1 A above the 2SH and 2S ring centers, respectively, and the thiol is aromatic. Although the thione is not aromatic, it is stabilized by the thioamide resonance. In solvent, the large 2S dipole, 2-3 times greater than 2SH, favors the thione tautomer and, in conclusion, 2S is thermodynamically more stable than 2SH in solution.     

Theoretical study of the enol imine <--> enaminone tautomeric equilibrium in organic solvents

The tautomeric enol imine <--> enaminone (phenol <--> quinone) equilibrium of the 1-hydroxy-2-naphthaldehyde Schiff base (2-phenyliminomethyl-naphthalen-1-ol) was investigated by density functional theory (B3LYP) and ab initio (MP2) methods in the IEF-PCM polarizable continuum dielectric solvent approximation and by a combined ab initio + FEP/MC study by considering an explicit solvent model. Special emphasis was put on the effect of solvation on this equilibrium by using an apolar (CCl4), polar aprotic (CH3CN), and polar protic (CH3OH) solvent. Compared with experimental tautomerization Gibbs free energies, the IEF-PCM/B3LYP calculations apparently overestimate the stability of the quinone form both when the 6-31G(d,p) and the 6-311++G(d,p) basis sets are applied. IEF-PCM/MP2 studies with the above basis sets predict the preference of the aromatic phenol tautomer, in contrast to the experiment in methanol and acetonitrile solvent. Calculation of the total relative free energy as DeltaG(tot) = DeltaE(int)(IEF-PCM/QCISD(T)/6-31G(d)) + DeltaG(solv, FEP/MC) + DeltaG(thermal) provided agreement with the experimental values up to 0.6 kcal/mol in the three solvents, and the predominant tautomer was always correctly predicted. In-solution relevant atomic charges, derived by a fit to the molecular electrostatic potential generated by the IEF-PCM/B3LYP/6-31G(d,p) wave function, show strong dependence on the fitting procedure (CHELPG or RESP) and are fairly insensitive to the chemical nature of the actual solvent. Use of the CHELPG charges in FEP/MC simulations revealed to be superior in comparison with the use of the RESP charge set.     

The influence of ionic surfactants on the acid-base properties and tautomeric equilibrium of 2-dimethylaminomethylphenol

Shifts in the acid-base and tautomeric equilibria have been observed in aqueous solutions of 2-dimethylaminomethylphenol (DAMP) containing surfactants. Cationic micelles of cetyltrimethylammonium bromide increase the dissociation constants of DAMP (pK₁ 0.3, pK₂ 0.5), and anionic micelles of sodium dodecyl sulfate reduce them (pK₁ 1.5, pK₂ 0.3). The constant of tautomeric equilibrium decreases when ionic surfactants are added. This is connected with the better solubilization of the neutral form by micelles.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1215–1218, July, 1994.     

Theoretical and spectroscopic study of 2-substituted indan-1,3-diones: a coherent picture of the tautomeric equilibrium

The structures of some 2-substituted indan-1,3-diones are investigated in the gas phase and solution using quantum chemical calculations and spectral (NMR, IR, and UV) measurements. The influence of the substituent at the 2-position on the tautomeric equilibrium of 2-substituted indan-1,3-diones in solvents with different polarity is evaluated. It is shown that the equilibrium in 2-formyl-indan-1,3-dione and 2-acetyl-indan-1,3-dione is shifted to the 2-hydroxyalkylidene-indan-1,3-dione tautomer, while 2-carboxyamide-indan-1,3-dione exists as a mixture of two tautomers, 2-(hydroxyaminomethylidene)-indan-1,3-dione and 2-carboamide-1-hydroxy-3-oxo-indan, with extremely fast proton transfer between them. The situation for 2-carboxy-indan-1,3-dione is quite different - on the basis of the analysis of the obtained results, the possible existence of an anionic form of 2-carboxy-indan-1,3-dione in solution can be inferred.     

Recent investigations and applications of azidoazomethine-tetrazole tautomeric equilibrium (microreview)

Chemistry of Heterocyclic Compounds - Recent investigations of azidoazomethine-tetrazole (azide-tetrazole) tautomeric equilibrium reported from 2014 to 2019 are summarized. Pyridine, pyrimidine,...