Concerning the solvent effect in the tautomerism of uracil, 5-fluorouracil, and thymine by density-functional theory and ab initio calculations

The tautomerism of uracil, 5-fluorouracil, and thymine has been investigated in the gas phase and in solution. Electron correlation effects were included in ab initio computations at the MP2 level, and DFT calculations were performed using the B3LYP level. Full geometry optimizations were conducted at the HF/6-31G**, HF/6-31+G**, and B3LYP/6-31+G** levels. Single-point MP2/6-31+G** calculations were performed on the HF/6-31+G** optimized geometries. The influence of the solvent was examined from self-consistent reaction field calculations performed with )=2.21 (1,4-dioxane) and )=78.54 (water). The calculated relative free energies ((G) indicate that substitution of uracil at the position group does not change the relative free energy order of the uracil tautomers in the gas phase and in 1,4-dioxane (except at the MP2 level) whereas this ordering changes in water. Attachment of a fluorine atom changes the relative free energy order of uracil tautomers in the gas phase and in solution.     

Evaluation of several economical computational methods for geometry optimization of phosphorus acid derivatives

Several economical methods for geometry optimisation, applicable to larger molecules, have been evaluated for phosphorus acid derivatives. MP2/cc-pVDZ and B3LYP/6-31+G(d) geometry optimizations are used as reference points, results from geometry optimizations for other methods and their subsequent single point energy calculations are compared to these references. The geometries from HF/MIDI! optimizations were close to those of the references and subsequent single point energies with B3LYP/6-31+G(d,p) or EDF1/6-31+G(d) gave a mean average deviation (MAD) of less than 0.5 kcal mol-1 from those obtained with the reference geometries.     

Study of the hydrogen bond in different orientations of adenine-thymine base pairs: An <Emphasis Type="Italic">ab initio</Emphasis> study

In order to gain deeper insight into structure, charge distribution, and energies of A-T base pairs, we have performed quantum chemical ab initio and density functional calculations at the HF (Hartree-Fock) and B3LYP levels with 3-21G*, 6-31G*, 6-31G**, and 6-31++G** basis sets. The calculated donor-acceptor atom distances in the Watson-Crick A-T base pair are in good agreement with the experimental mean values obtained from an analysis of 21 high resolution DNA structures. In addition, for further correction of interaction energies between adenine and thymine, the basis set superposition error (BSSE) associated with the hydrogen bond energy has been computed via the counterpoise method using the individual bases as fragments. In the Watson-Crick A-T base pair there is a good agreement between theory and experimental results. The distances for (N2...H23-N19), (N8-H13...O24), and (C1...O18) are 2.84, 2.94, and 3.63 A, respectively, at B3LYP/6-31G** level, which is in good agreement with experimental results (2.82, 2.98, and 3.52 A). Interaction energy of the Watson-Crick A-T base pair is -13.90 and -10.24 kcal/mol at B3LYP/6-31G** and HF/6-31G** levels, respectively. The interaction energy of model (9) A-T base pair is larger than others, -18.28 and -17.26 kcal/mol, and for model (2) is the smallest value, -13.53 and -13.03 kcal/mol, at B3LYP/6-31G** and B3LYP/6-31++G** levels, respectively. The computed B3LYP/6-31G** bond enthalpies for Watson-Crick A-T pairs of -14.4 kcal/mol agree well with the experimental results of -12.1 kcal/mol deviating by as little as -2.3 kcal/mol. The BSSE of some cases is large (9.85 kcal/mol) and some is quite small (0.6 kcal/mol).     

Post Hartree-Fock studies of the canonical Watson-Crick DNA base pairs: molecular structure and the nature of stability

Gas-phase gradient optimization was carried out on the canonical Watson-Crick DNA base pairs using the second-order M?ller-Plesset perturbation method at the 6-31G(d) and 6-31G(d,p) basis sets. It is detected that full geometry optimization at the MP2 level leads to an intrinsically nonplanar propeller-twisted and buckled geometry of G-C and A-T base pairs; while HF and DFT methods predict perfect planar or almost planar geometry of the base pairs. Supposedly the nonplanarity of the pairs is caused by pyramidalization of the amino nitrogen atoms, which is underestimated by the HF and DFT methods. This justifies the importance of geometry optimization at the MP2 level for obtaining reliable prediction of the charge distribution, molecular dipole moments and geometrical structure of the base pairs. The Morokuma-Kitaura and the Reduced Variational Space methods of the decomposition for molecular HF interaction energies were used for investigation of the hydrogen bonding in the Watson-Crick base pairs. It is shown that the HF stability of the hydrogen-bonded DNA base pairs originates mainly from electrostatic interactions. At the same time, the calculated magnitude of the second order intramolecular correlation correction to the Coulomb energy showed that electron correlation reduces the contribution of the electrostatic term to the attractive interaction for the A-T and G-C base pairs. Polarization, charge transfer and dispersion interactions also make considerable contribution to the attraction energy of bases.     

Quantum mechanical and NMR spectroscopy studies on the conformations of the hydroxymethyl and methoxymethyl groups in aldohexosides

The potential energy surfaces of the hydroxymethyl and methoxymethyl groups in methyl hexopyranosides have been extensively studied, employing quantum mechanical calculations and high resolution NMR data. The structure and energy of the C-5-C-6 rotamers were calculated at the B3LYP level of the density functional theory (DFT). For all, geometry optimizations were carried out for 264 conformers of 16 methyl D-gluco- and methyl D-galactopyranoside derivatives 1-16 at the B3LYP/6-31G** level. For all calculated minima, single-point calculations were performed at the B3LYP/6-311++G** level. Solvent effects were considered using a self-consistent reaction field method. Values of the vicinal coupling constants 3J(H-5-H-6R), 3J(H-5-H-6S), 3J(C-4-H-6R), and 3J(C-4-H-6S) for methyl D-glucopyranosides, methyl D-galactopyranosides and their 6-O-methyl derivatives 9-16 were measured in two solvents, methanol and water. The calculated gg, gt, and tg rotamer populations of the hydroxymethyl and methoxymethyl groups in 9-16 agreed well with experimental data. The results clearly showed that the population of gg, gt, and tg rotamers is sensitive to solvent effects. It was concluded that the preference of rotamers in 1-16 is due to the hydrogen bonding and solvent effects.     

Post Hartree-Fock Studies of the Canonical Watson-Crick DNA Base Pairs: Molecular Structure and the Nature of Stability

Abstract

Gas-phase gradient optimization was carried out on the canonical Watson-Crick DNA base pairs using the second-order Møller-Plesset perturbation method at the 6–31G(d) and 6- 31G(d,p) basis sets. It is detected that full geometry optimization at the MP2 level leads to an intrinsically nonplanar propeller-twisted and buckled geometry of G-C and A-T base pairs; while HF and DFT methods predict perfect planar or almost planar geometry of the base pairs. Supposedly the nonplanarity of the pairs is caused by pyramidalization of the amino nitrogen atoms, which is underestimated by the HF and DFT methods. This justifies the importance of geometry optimization at the MP2 level for obtaining reliable prediction of the charge distribution, molecular dipole moments and geometrical structure of the base pairs. The Morokuma-Kitaura and the Reduced Variational Space methods of the decomposition for molecular HF interaction energies were used for investigation of the hydrogen bonding in the Watson-Crick base pairs. It is shown that the HF stability of the hydrogen-bonded DNA base pairs originates mainly from electrostatic interactions. At the same time, the calculated magnitude of the second order intramolecular correlation correction to the Coulomb energy showed that electron correlation reduces the contribution of the electrostatic term to the attractive interaction for the A-T and G-C base pairs. Polarization, charge transfer and dispersion interactions also make considerable contribution to the attraction energy of bases.     

Theoretical study on the ground state intramolecular proton transfer (IPT) and solvation effect in two Schiff bases formed by 2-aminopyridine with 2-hydroxy-1- naphthaldehyde and 2-hydroxy salicylaldehyde

The tautomerization mechanism the isolated and monohydrated forms of two Schiff bases 1 and 2, and the effect of solvation on the proton transfer from enol-imine form to the keto-enamine form have been investigated using the B3LYP hybrid density functional method at the 6-31G** basis set level. The barrier heights for H₂O-assisted reactions are significantly lower than that of unassisted tautomerization reaction in the gas phase. Nonspecific solvent effects have also been taken into account by using the continuum model (IPCM) of four different solvent. The tautomerization energies and the potential energy barriers are decreased by increasing solvent polarity. Figure The tautomerization mechanism the isolated and monohydrated forms of two Schiff bases 1 and 2, and the effect of solvation on the proton transfer from enol-imine form to the keto-enamine form have been investigated using the B3LYP hybrid density functional method at the 6-31G** basis set level     

Molecular conformational analyses of dehydroalanine analogues

The conformational preferences of dehydroalanine (ΔAla) were examined through ab initio calculations. The geometries of the minimum energy conformations for N-formyldehydro alanilamide and N-acetyl-N′-methylamide of dehydroalanine were determined by gradient optimization at the HF/6-31G* level, and correlation corrections were examined with MP2 single-point energy calculations. Furthermore, HF/3-21G ab initio geometry optimizations were performed on nine conformations of the model tripeptide N-acetyl-N′-methylamide of didehydroalanine. The results indicate that the C₅ is the lowest energy conformation at all levels of theory. However, the relative energy of the helix conformation decreases when the number of ΔAla residues in the peptide chain increases. On the other hand, significant variations of the geometry upon conformational change were observed for the three compounds investigated. These results permit to extract important conformationally dependent geometry trends. The results of this study were compared to x-ray diffraction data on single crystals of dehydroalanine-containing peptides. © 1995 John Wiley & Sons, Inc.     

The effects of tetraalkylammonium salts on helix-coil transition parameters in natural and synthetic ribo- and deoxyribo-polynucleotides

Thermal transition profiles were recorded for a variety of natural and synthetic DNA and double-stranded RNA preparations in the presence of tetramethylammonium (TMA+) and tetraethylammonium (TEA+) cations. Double-stranded RNAs of natural origin, with GC contents of 50% exhibited the same profiles and Tm values as native DNA containing normal bases. Hence the tetraalkylammonium cations liquidate not only the effects of base composition, and the difference in stability between A-T and A-U base pairs (further confirmed by measurements with uracil-containing DNA from phage PBS-2), but also that of the 2'OH. In the presence of TMA+ cations, there is very marked enhancement of the stability of U-U base pairs in poly(rU) and poly(Um). In 2.4 M TEA, the 1:1 complex of poly(G) with poly (C) formed readily and melted reversibly with a Tm as low as 87 degrees C. At concentrations of TMA and TEA for which dTm/dXGC = 0, the Tm values for various phage DNA preparations containing atypical bases (phages T2, T4, phi e, phi W-14, PBS-2) differ appreciably from those with 'normal bases'. Analysis of these findings indicates that the selective interaction of TMA and TEA cations with A-T base pairs occurs in the minor groove of the DNA helix. The overall results show that the action of these quaternary ammonium cations is not due exclusively to preferential binding to A-T base pairs, but must involve other factors, including modifications of solvent structure. They also underline the utility of TMA and TEA solvent systems for placing in evidence transition profiles not accessible in other solvent systems.     

A theoretical study on the activation of Ser70 in the acylation mechanism of cephalosporin antibiotics

A computational study using some molecular modeling and quantum mechanical methods has been performed for determining the most favor activation process for Ser70 in the acylation mechanism for the cephalosporin antibiotics among the three proposed ones given in the literature. The computation is based on an X-ray structure of the B chain of the Bacillus licheniformis BS3 beta-lactamase-cefoxitin complex. The position of a catalytic water involved in one of the reaction mechanism is defined using the Grid20 and InsightII programs, while that of the truncated ligand is defined using the InsightII and FirstDiscovery programs. The geometry of structures of each reaction scheme is optimized at the HF/3-21 G level of theory, and then the single point energy for each reactive species in each reaction scheme is computed at the levels of HF/6-31 + G (3df, 2p) and B3LYP/6-31 + G (3df, 2p). The effect of solvent on each reaction scheme is also studied by comparing the calculation results for each reaction scheme either in gas phase or in solution using the HF/6-31 + G (3df, 2p) level of theory. A computation using the B3LYP/6-31 + G (3df, 2p) level of theory and the Polarized Continuum Model (PCM) and by treating water as a solvent is also conducted for each activation process. It is found that, energetically, the most favor activation process for Ser70 in the acylation mechanism is the one where a proton transfer is mediated by the catalytic water and the catalytic residues Glu166 and Ser70. This agrees with those observed in an ultrahigh resolution X-ray structure and a QM/MM theoretical study published recently on the same acylation process.     

Structure and the energy of base pairing in non-natural bases of nucleic acids: the azaguanine-cytosine and azaadenine-thymine base pairs

Watson-Crick optimized geometries and the energies of base pairing for the natural pairs of nucleic bases: adenine-thymine (AT) and guanine-cytosine (GC) have been recalculated by ab initio methods in order to compare results to those found for the non-natural azaadenine-thymine (AAT) and azaguanine-cytosine (AGC) pairs. Geometry optimizations carried out at the HF/6-31G** level and energies obtained at MP2/6-31G**, show that AAT and AGC have hydrogen bonding patterns similar to the natural AT and GC and that the interaction energies (DeltaH0int) for the former are ca. 7 kcal/mol more stable than the latter. Accordingly, the pairs based on azapurines would be favored with respect to the natural pairs. Some possible explanations why nature does not use extensively the azabases in base pairing are given.     

Theoretical Investigation of the Molecular Structure of the πκ DNA Base Pair

Abstract

The structure of the nonclassical πκ base pair (7–methyl-oxoformycin … 2,4-diaminopyrimidine) was studied at the ab initio Hartree-Fock (HF) and MP2 levels using the 6–31G* and 6–31G** basis sets. The πκ base pair is bound by three parallel hydrogen bonds with the donor-acceptor-donor recognition pattern. Recently, these bases were proposed as an extension of the genetic alphabet from four to six letters (Piccirilli et al. Nature 343, 33(1990)). By the HF/6- 31G* method with full geometry optimization we calculated the 12 degree propeller twist for the minimum energy structure of this complex. The linearity of hydrogen bonds is preserved in the twisted structure by virtue of the pyramidal arrangement of the κ-base amino groups. The rings of both the π and κ molecules remain nearly planar. This nonplanar structure of the πκ base pair is only 0.1 kcal/mol more stable than the planar (Cs) conformation. The HF/6- 31G* level gas-phase interaction energy of πκ (—13.5 kcal/mol) calculated by us turned out to be nearly the same as the interaction energy obtained previously for the adenine-thymine base pair (—13.4 kcal/mol) at the same computational level. The inclusion of p-polarization functions on hydrogens, electron correlation effects (MP2/6–31G** level), and the correction for the basis set superposition error (BSSE) increase this energy to -14.0 kcal/mol.     

Theoretical ab initio study of the effects of methylation on structure and stability of G:C Watson-Crick base pair

Methylation of DNA occurs most readily at N(3), N(7), and O(6) of purine bases and N(3) and O(2) of pyrimidines. Methylated bases are continuously formed through endogenous and exogenous mechanisms. The results of a theoretical ab initio study on the methylation of G:C base pair components are reported. The geometries of the local minima were optimized without symmetry restrictions by the gradient procedure at DFT level of theory and were verified by energy second derivative calculations. The standard 6-31G(d) basis set was used. The single-point calculations have been performed at the MP2/6-31G(d,p), MP2/6-31++G(d,p), and MP2/6-311++G(2d,2p) levels of theory. The geometrical parameters, relative stability and counterpoise corrected interaction energies are reported. Also, using a variation-perturbation energy decomposition scheme we have found the vital contributions to the total interaction energy.     

A critical role for Pin2/TRF1 in ATM-dependent regulation. Inhibition of Pin2/TRF1 function complements telomere shortening, radiosensitivity, and the G(2)/M checkpoint defect of ataxia-telangiectasia cells.

Cells derived from patients with the human genetic disorder ataxia-telangiectasia (A-T) display many abnormalities, including telomere shortening, premature senescence, and defects in the activation of S phase and G(2)/M checkpoints in response to double-strand DNA breaks induced by ionizing radiation. We have previously demonstrated that one of the ATM substrates is Pin2/TRF1, a telomeric protein that binds the potent telomerase inhibitor PinX1, negatively regulates telomere elongation, and specifically affects mitotic progression. Following DNA damage, ATM phosphorylates Pin2/TRF1 and suppresses its ability to induce abortive mitosis and apoptosis (Kishi, S., Zhou, X. Z., Nakamura, N., Ziv, Y., Khoo, C., Hill, D. E., Shiloh, Y., and Lu, K. P. (2001) J. Biol. Chem. 276, 29282-29291). However, the functional importance of Pin2/TRF1 in mediating ATM-dependent regulation remains to be established. To address this question, we directly inhibited the function of endogenous Pin2/TRF1 in A-T cells by stable expression of two different dominant-negative Pin2/TRF1 mutants and then examined their effects on telomere length and DNA damage response. Both the Pin2/TRF1 mutants increased telomere length in A-T cells, as shown in other cells. Surprisingly, both the Pin2/TRF1 mutants reduced radiosensitivity and complemented the G(2)/M checkpoint defect without inhibiting Cdc2 activity in A-T cells. In contrast, neither of the Pin2/TRF1 mutants corrected the S phase checkpoint defect in the same cells. These results indicate that inhibition of Pin2/TRF1 in A-T cells is able to bypass the requirement for ATM in specifically restoring telomere shortening, the G(2)/M checkpoint defect, and radiosensitivity and demonstrate a critical role for Pin2/TRF1 in the ATM-dependent regulation of telomeres and DNA damage response.     

Fine mapping of the chromosome 11q22-23 region using PFGE, linkage and haplotype analysis; localization of the gene for ataxia telangiectasia to a 5cM region flanked by NCAM/DRD2 and STMY/CJ52.75, phi 2.22.

Using pulsed-field gel electrophoresis, and a range of different enzyme digests, we have established that both markers of each of the pairs CJ52.208/YNB3.12, NCAM/DRD2, and STMY/CJ52.75, on chromosome 11q22-23, show physical linkage on a single DNA fragment. We have also shown, using genetic linkage and haplotype analyses, that these markers lie within a region of approximately 18cM, which, it has been shown previously, is likely to contain the A-T gene. The relative positions of these marker loci, and the distance between them was determined in order to construct a detailed map which has allowed a more precise localization of the A-T gene. We have shown that in pairwise linkage analysis the strongest support for linkage to the A-T gene was with the STMY/CJ52.75 locus (Z = 5.59, theta = 0.0). A three-point analysis using the results from STMY/CJ52.75 and the closely linked marker phi 2.22 gave Z = 5.55, theta = 0.03. Despite persisting evidence of some linkage to Thy-1 our results are consistent with the existence of a single A-T locus on chromosome 11q22-23 and our best estimate of the position of this locus places it between NCAM/DRD2 and (STMY/CJ52.75, F2.22) (Z = 6.74), a region of approximately 5cM in males.     

Structure and absolute configuration of ginkgolide B characterized by IR‐ and VCD spectroscopy

Experimental and calculated (B3LYP/6‐31G(d)) vibrational circular dichroism (VCD) and IR spectra are compared, illustrating that the structure and absolute configuration of ginkgolide B (GB) may be characterized directly in solution. A conformational search for GB using MacroModel and subsequent DFT optimizations (B3LYP/6‐31G(d)) provides a structure for the lowest energy conformer which agrees well with the structure determined by X‐ray diffraction. In addition, a conformer at an energy of 7 kJ mol^?1 (B3LYP/6‐311+G(2d,2p)) with respect to the lowest energy conformer is predicted, displaying different intramolecular hydrogen bonding. Differences between measured and calculated IR and VCD spectra for GB at certain wavenumbers are rationalized in terms of interactions with solvent, intermolecular GB‐GB interactions, and the potential presence of more than one conformer. This is the first detailed investigation of the spectroscopic fingerprint region (850?1300 cm^?1) of the natural product GB employing infrared absorption and VCD spectroscopy. Chirality, 2010. © 2009 Wiley‐Liss, Inc.     

Theoretical modeling and experimental studies on N-n-Decyl-2-oxo-5-nitro-1-benzylidene-methylamine

The Schiff base compound, N-n-Decyl-2-oxo-5-nitro-1-benzylidene-methylamine, has been -synthesized and characterized by IR, electronic spectroscopy, and X-ray single-crystal determination. Molecular geometry from X-ray experiment of the title compound in the ground state have been compared using the Hartree-Fock (HF) and density functional method (B3LYP) with 6-31G(d) basis set. Calculated results show that density functional theory (DFT) at B3LYP/6-31G(d) level can well reproduce the structure of the title compound. To investigate the solvent effect for the atomic charge distributions of the title compound, self-consistent reaction field theory with Onsager reaction field model was used. In addition, DFT calculations of the title compound, molecular electrostatic potential and thermodynamic properties were performed at B3LYP/6-31G(d) level of theory.     

Comparison of gamma-radiation-induced accumulation of ataxia telangiectasia and control cells in G2 phase

Recent reports from a number of laboratories have linked radiosensitivity in ataxia telangiectasia (A-T) to a large and prolonged block of some cells in G2 phase. Previous results from this laboratory, largely with one Epstein-Barr virus-transformed A-T lymphoblastoid cell line, presented evidence for a dramatic increase in the number of cells in G2 phase over controls during a 24-h period post irradiation. We describe here a study of the effect of gamma-radiation on G2 phase delay in several A-T cell lines. Based on previous results with several cell lines 24 h post irradiation was selected as the optimum time to discriminate between G2 phase delay in control and A-T cells. All A-T homozygotes showed a significantly greater number of cells in G2 phase, 24 h post irradiation, than observed in controls. A more prolonged delay in G2 phase after irradiation was seen in different A-T cell types that included lymphoblastoid cells, fibroblasts and SV40-transformed fibroblasts. At the radiation dose used it was not possible to distinguish A-T heterozygotes from controls.     

EVALUATION OF SEVERAL ECONOMICAL COMPUTATIONAL METHODS FOR GEOMETRY OPTIMISATION OF PHOSPHORUS ACID DERIVATIVES

Several economical methods for geometry optimisation, applicable to larger molecules, have been evaluated for phosphorus acid derivatives. MP2/cc-pVDZ and B3LYP/6-31+G(d) geometry optimisations are used as reference points, results from geometry optimisations for other methods and their subsequent single point energy calculations are compared to these references. The geometries from HF/MIDI! optimisations were close to those of the references and subsequent single point energies with B3LYP/6-31+G(d,p) or EDF1/6-31+G(d) gave a mean average deviation (MAD) of less than 0.5 kcal mol^?1 from those obtained with the reference geometries.