Conformational study of erythritol and threitol in the gas state by density functional theory calculations

Density functional theory calculations using the B3LYP functional and the 6-311++G(d,p) basis set were carried out on the isolated molecules of erythritol and L-threitol. For the meso isomer, a relatively large number of conformers have to be considered to describe the gas state structure. The lowest energy conformer is characterized by the establishment of a strong intramolecular H-bond between the two terminal hydroxyl groups, giving rise to a seven-membered ring and two additional weaker H-bonds between vicinal OH groups. In the case of L-threitol, two conformers are predominant in the gas state, and both are stabilized by the formation of a cyclic system of four intramolecular hydrogen bonds involving all OH groups. The conformational stability in both diastereomers is discussed in terms of the electronic energy and of the Gibbs energy. The weighted mean enthalpy of both diastereomers in the gas state at 298.15 K was obtained from the thermodynamic data and Boltzmann populations of the low-energy conformers.     

Conformational preferences of α,α-trehalose in gas phase and aqueous solution

This work presents an investigation on the conformational preferences of α,α-trehalose in gas phase and aqueous solution. Eighty-one systematically selected structures were studied at the B3LYP/6-311++G(d,p)//B3LYP/6-31G(d) level, giving rise to 40 unique conformers. The 19 lower energy structures and some selected other were further re-optimized at the B3LYP/6-311++G(d,p) level. The main factors accounting for the conformer’s stability were pointed out and discussed. NBO and QTAIM analyses were performed in some selected conformers in order to address the anomeric and exo-anomeric effects as well as intramolecular hydrogen bonding. The effect of solvent water on the relative stability of the conformers was accounted for by applying the conductor-like polarizable continuum model, CPCM.     

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.     

Zwitterionic conformers of pyrrolysine and their interactions with metal ions—a theoretical study

A total of 16 pyrrolysine conformers in their zwitterionic forms are studied in gas and simulated aqueous phase using a polarizable continuum model (PCM). These conformers are selected on the basis of our study on the intrinsic conformational properties of non-ionic pyrrolysine molecule in gas phase [Das and Mandal (2013) J Mol Model 19:1695?1704]. In aqueous phase, the stable zwitterionic pyrrolysine conformers are characterized by full geometry optimization and vibrational frequency calculations using B3LYP/6-311++G(d,p) level of theory. Single point calculations are also carried out at MP2/6-311++G(d,p) level. Characteristic intramolecular hydrogen bonds present in each conformer, their relative energies, theoretically predicted vibrational spectra, rotational constants and dipole moments are systematically reported. The calculated relative energy range of the conformers at B3LYP/6-311++G(d,p) level is 5.19 kcal mol^?1 whereas the same obtained by single point calculations at MP2/6-311++G(d,p) level is 4.58 kcal mol^?1. A thorough analysis reveals that four types of intramolecular H-bonds are present in the conformers; all of which play key roles in determining the energetics and in imparting the observed conformations to the conformers. The vibrational frequencies are found to shift invariably toward the lower side of frequency scale corresponding to the presence of the H-bonds. This study also points out that conformers with diverse structural motifs may differ in their thermodynamical stability by a narrow range of relative energy. The effects of metal coordination on the relative stability order and structural features of the conformers are examined by complexing five zwitterionic conformers of pyrrolysine with Cu⁺² through their carboxylate groups. The interaction enthalpies and Gibbs energies, rotational constants, vibrational frequencies and dipole moments of the metal complexes calculated at B3LYP level are also reported. The zwitterionic conformers of pyrrolysine are not stable in gas phase; after geometry optimization they are converted to the non-ionic forms.     

DFT studies on the intrinsic conformational properties of non-ionic pyrrolysine in gas phase

B3LYP/6-31G(d,p) level of theory is used to carry out a detailed gas phase conformational analysis of non-ionized (neutral) pyrrolysine molecule about its nine internal back-bone torsional angles. A total of 13 minima are detected from potential energy surface exploration corresponding to the nine internal back-bone torsional angles. These minima are then subjected to full geometry optimization and vibrational frequency calculations at B3LYP/6-31++G(d,p) level. Characteristic intramolecular hydrogen bonds present in each conformer, their relative energies, theoretically predicted vibrational spectra, rotational constants and dipole moments are systematically reported. Single point calculations are carried out at B3LYP/6-311++G(d,p) and MP2/6-31++G(d,p) levels. Six types of intramolecular H-bonds, viz. O…H–O, N…H-O, O…H–N, N…H–N, O…H–C and N…H–C, are found to exist in the pyrrolysine conformers; all of which contribute to the stability of the conformers. The vibrational frequencies are found to shift invariably toward the lower side of frequency scale corresponding to the presence of intramolecular H-bond interactions in the conformers.     

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.     

Low-energy conformers of pamidronate and their intramolecular hydrogen bonds: a DFT and QTAIM study

Extensive DFT and ab initio calculations were performed to characterize the conformational space of pamidronate, a typical pharmaceutical for bone diseases. Mono-, di- and tri-protic states of molecule, relevant for physiological pH range, were investigated for both canonical and zwitterionic tautomers. Semiempirical PM6 method were used for prescreening of the single bond rotamers followed by geometry optimizations at the B3LYP/6-31++G(d,p) and B3LYP/6-311++G(d,p) levels. For numerous identified low energy conformers the final electronic energies were determined at the MP2/6-311++G(2df,2p) level and corrected for thermal effects at B3LYP level. Solvation effects were also considered via the COSMO and C-PCM implicit models. Reasonable agreement was found between bond lengths and angle values in comparison with X-ray crystal structures. Relative equilibrium populations of different conformers were determined from molecular partition functions and the role of electronic, vibrational and rotational degrees of freedom on the stability of conformers were analyzed. For no level of theory is a zwitterionic structure stable in the gas-phase while solvation makes them available depending on the protonation state. Geometrically identified intramolecular hydrogen bonds were analyzed by QTAIM approach. All conformers exhibit strong inter-phosphonate hydrogen bonds and in most of them the alkyl-amine side chain is folded on the P-C-P backbone for further hydrogen bond formation.

Absolute configuration of eremophilanoids by vibrational circular dichroism

The absolute configurations (AC) of natural occurring 6-hydroxyeuryopsin (1), of its acetyl derivative 2, and of eremophilanolide 8 were confirmed by comparison of the experimental vibrational circular dichroism (VCD) spectra with theoretical curves generated from density functional theory (DFT) calculations. Initial analyses were carried out using a Monte Carlo searching with the MMFF94 molecular mechanics force field. All MMFF94 conformers were further optimized using DFT at the B3LYP/6-31G(d) level of theory, followed by calculations of their vibrational frequencies at the B3LYP/6-31G(d,p); the VCD spectra of 2 and 8 were also calculated at the B3PW91/DGDZVP level of theory. Good agreement between theoretical and experimental VCD curves unambiguously verified the 4S,5R,6S absolute configuration for 1 and 2, and the 1S,4S,5R,6S,8S,10S configuration for 8.     

Density functional conformational study of 2-O-sulfated 3,6 anhydro-α-D-galactose and of neo-κ- and ι-carrabiose molecules in gas phase and water

We examined the conformational preferences of the 2-O-sulfated-3,6-α-D-anhydrogalactose (compound I) and two 1,3 linked disaccharides constituting-κ or ι-carrageenans using density functional and ab initio methods in gas phase and aqueous solution. Systematic modifications of two torsion angles leading to 324 and 144 starting geometries for the compound I and each disaccharide were used to generate adiabatic maps using B3LYP/6-31G(d). The lower energy conformers were then fully optimized using B3LYP, B3PW91 and MP2 with several basis sets. Overall, we discuss the impact of full relaxation on the energy and structure of the dominant conformations, present the performance comparison with previous molecular mechanics calculations if available, and determine whether our results are impacted, when polarization and diffuse functions are added to the 6-31G(d) basis set, or when the MP2 level of theory is used.     

Conformational analysis of perezone and dihydroperezone using vibrational circular dichroism

The vibrational circular dichroism (VCD) spectra of perezone and dihydroperezone measured from CDCl₃ solutions were quite similar, suggesting analogous conformations for both molecules. Their absolute configurations were confirmed by comparison of the experimental VCD spectrum of each compound with curves generated from theoretical calculations using density functional theory (DFT) at the B3LYP/DGDZVP level of theory taking into account their conformational mobility. Conformational analysis of the 8-(R) enantiomer showed 19 low energy conformers in a 2.4 kcal/mol energy range, while for 8-(R), with the saturated side alkyl chain, 34 conformers were considered in the first 2 kcal/mol. Initial analyses were carried out using a Monte Carlo searching with the MMFF94 molecular mechanics force field, all MMFF94 conformers were geometrically optimized using DFT at the B3LYP/6-31G(d) level of theory, followed by reoptimization and calculations of their vibrational frequencies at the B3LYP/DGDZVP level. Good agreement between the theoretical 8-(R) enantiomers and experimental VCD curves were observed for both.     

Substituent effects on the properties of fluorene-thieno[3,4-b]pyrazine derivatives for light-emitting applications

Five thieno[3,4-b]pyrazine-based model compounds were studied to explore the effects of the substituent groups (alkyl or aryl) on the structure, atomic charge, optical properties, ionization potential (IP), electron affinity (EA), and reorganization energy. Theoretical calculations were carried out by density functional theory (DFT) using the B3LYP hybrid function combined and CAM-B3LYP with the 6-31G(d) basis set. The lowest-lying absorption and emission spectra of 9,9'-diethylhexylfluorene-alt-5,7-dithien-2-yl-thieno[3,4-b] pyrazine (FDDTTP) with alkyl groups showed a blue-shift, while those of FDDTTP with aryl groups exhibited a red-shift. The results agree well with analytical data from reorganization energies. IPs are brought down by both alkyl and aryl groups. However, EAs are raised only by aryl units. The results indicate that aryl groups are more helpful in forming excitions for FDDTTP molecules. Consequently, FDDTTP with aryl groups are more efficient acceptor segments for designing donor-acceptor copolymers than those with alkyl groups.     

Experimental and quantum chemical calculational studies on 2-[(4-Fluorophenylimino)methyl]-3,5-dimethoxyphenol

The Schiff base compound, 2-[(4-Fluorophenylimino)methyl]-3,5-dimethoxyphenol, 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) and HF can well reproduce the structure of the title compound. The energetic behavior of the title compound in solvent media has been examined using B3LYP method with the 6–31G(d) basis set by applying the polarizable continuum model (PCM). The total energy of the title compound decrease with the increasing polarity of the solvent. By using TD-DFT and TD-HF methods, electronic absorption spectra of the title compound have been predicted and a good agreement with the TD-DFT method and the experimental ones is determined. In addition, DFT calculations of the title compound, molecular electrostatic potential (MEP), natural bond orbital (NBO), and thermodynamic properties were performed at B3LYP/6–31G(d) level of theory.     

Electronic structure and conformational properties of <Emphasis Type="Italic">1H</Emphasis>-indole-3-acetic acid

The conformational space of 1H-Indole-3-Acetic Acid (IAA) was scanned using molecular dynamics at semiempirical level, and complemented with functional density calculations at B3LYP/6-31G** level, 14 conformers of lowest energy were obtained. Electronic distributions were analyzed at a higher calculation level, thus improving the basis set (B3LYP/6-311++G**). A topological study based on Bader’s theory (AIM: atoms in molecules) and natural bond orbital (NBO) framework performed with the aim to analyze the stability and reactivity of the conformers allowed the understanding of electronic aspects relevant in the study of the antioxidant properties of IAA. Intramolecular hydrogen bonds were found and were characterized as blue-shifting hydrogen bonding interactions. Furthermore, molecular electrostatic potential maps (MEPs) were obtained and analyzed in the light of AIM and NBO results, thus showing subtle but essential features related not only to reactivity but also with intramolecular weak interactions, charge delocalization and structure stabilization.     

The (α-1,6) glycosidic bond of isomaltose: a tricky system for theoretical conformational studies

Stable conformations of β-isomaltose (α-d-glucopyranosyl-(1→6)-β-d-glucose) in gas-phase and aqueous solution are investigated in this study using quantum mechanical calculations. Conformational maps are calculated at HF/6-31G(d,p) level and lower energy structures are sampled in the most stable regions. Entropic and thermal corrections are considered and the Boltzmann population is obtained for conformers that are representative of the 18 most stable regions found on the potential energy surface. B3LYP/6-31+G(d,p) and B3LYP/6-311+G(2d,2p) calculations are used in conformational samplings. Solvation effects are considered through the polarizable continuum model approach. Hydroxymethyl group orientations are investigated for the most stable conformers. The influence of electronic correlation and solvation on the glycosidic linkage preference (TG, GT, and GG) and hydroxymethyl group orientation (tg, gt, and gg) are discussed. Heteronuclear spin coupling constants (³J_C,H) along the glycosidic linkage are calculated and comparison with other theoretical results and experiments is used to validate the obtained structures.     

Fluoro-substitution effects in deoxyfluoro-D-glucose derivatives: random conformational search and quantum chemical calculation

The effect of substitution by the fluorine atom at different positions of D-glucose was investigated by quantum chemical calculation of the low-energy conformers. These were obtained through the Random conformational search method. The geometries of conformers were optimized at the RHF/6-31(d) level, then reoptimization and vibrational analysis were performed at the B3LYP/6-31+G(d) level. Single-point energies were calculated at the B3LYP/6-311++G(2d,2p) level. The free energies of solvation in water were calculated utilizing the AM1-SM5.4 solvation model. For all substitution positions, the ring conformation does not change much, and the pyranoid 4C1 conformers are dominant, while variations in the substitution site result in different effects in the network of hydrogen bonds, anomeric effect, the solvation free energy, and the ratio of alpha- and beta-anomers.     

Absolute configuration of (−)-myrtenal by vibrational circular dichroism

The VCD spectrum of the monoterpene (−)-myrtenal (1) was compared with theoretical spectra using ab initio density functional theory (DFT) calculations at the B3LYP/6-31G(d,p), B3LYP/6-31G+(d,p), B3LYP/6-311G+(d,p), B3LYP/DGDZVP, and B3PW91/DGTZVP levels of theory. Conformational analysis of 1 indicated that the lowest energy conformer was s-trans-C2-C10, which contributes more than 98.5% to the total conformational population regardless of the employed level of theory. The use of a recently developed confidence level algorithm demonstrated that VCD spectra calculated for the main conformer, using the indicated hybrid functionals and basis set, gave no significant changes, from where it follows that B3LYP/DGDZVP calculations provide a superior balance between computer cost and VCD spectral accuracy. The DGDZVP basis set demanded around a quarter the time than the 6-311G+(d,p) basis set while providing similar results. The spectral comparison also provided evidence that the levorotatory enantiomer of myrtenal has the 1R absolute configuration.     

Computational Study of the Sulfonylated Amino Acid Hydroxamates Binding to the Zinc Ion within the Active Site of Carbonic Anhydrase

Abstract

The B3LYP/6–311+G(d,p) method and three ONIOM extrapolation methods ONI-OM (B3LYP/6–311+G(d,p): AM1); ONIOM(B3LYP/6–311+G(d,p): MNDO); ONIOM (B3LYP/6–311+G(d,p): HF/3-21G(d)) were used to characterize the complexes of Zn²⁺ cation with anionic sulfonylated amino acid hydroxamates (RSO₂NH-AA-CON(-)OH), possessing an unsubstituted RSO₂NH—amino acyl moiety. According to the R moiety we distinguish between pentafluorophenyl and 4-methoxyphenyl derivates. The amino acid hydroxamates included in the study were the Gly, Ala, and Leu derivates. Of the inhibitors investigated, the weakest zinc affinity exhibits the pentafluorophenyl derivate with Gly amino acid and the strongest affinity the 4-methoxyphenyl derivate with Leu amino acid. The inhibitors form bidentate coordination bonds with the zinc cation by means of the sulfonyl oxygen and the ionized hydroxamate nitrogen atoms, respectively. The zinc affinities computed using the B3LYP/6–311 +G(d,p)//HF/6–31 +G(d,p) method are in very good agreement with the full density functional theory (DFT) B3LYP/6–311+G(d,p)//B3LYP/6- 311+G(d,p) method and this method can be adopted to model larger complexes of inhibitors with the active site of carbonic anhydrase.     

NMR structure of the Euplotes raikovi pheromone Er-23 and identification of its five disulfide bonds.

The NMR solution structure of the 51 residue pheromone Er-23 from the ciliated protozoan Euplotes raikovi (Er) was calculated with the torsion angle dynamics program DYANA from 582 nuclear Overhauser enhancement (NOE) upper limit distance constraints, 46 dihedral angle constraints and 30 disulfide bond constraints. The disulfide bridges had not been assigned by chemical methods, and initially were assigned tentatively on the basis of inspection of the positioning of the Cys sulfhydryl groups in a bundle of 20 conformers that was calculated without disulfide bond constraints. The assignment of disulfide bridges was then validated by structure calculations that assessed the compatibility of plausible alternative Cys-Cys disulfide combinations with the input of NOE upper distance constraints and dihedral angle constraints. For a group of 20 conformers used to characterize the solution structure, the average pairwise root-mean-square distances from the mean coordinates calculated for the backbone heavy atoms N, C(alpha) and C' of resideus 1-51 is 0.38 A. The molecular architecture consists of a three-dimensional arrangement of five helices comprised of residues 2-8, 14-17, 26-29, 34-36 and 38-47, with five disulfide bridges in the positions 3-24, 6-16, 13-47, 27-40, and 35-51, which has so far not been represented in the Protein Data Bank. Er-23 is unique among presently known Er-pheromones with respect to size, sequence, the number of disulfide bonds and the three-dimensional structure, thus providing a new structural basis for rationalizing the physiological functions of this protein family.