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.     

Studies on molecular structure and tautomerism of a vitamin B<Subscript>6</Subscript> analog with density functional theory

This work presents a computational study on the molecular structure and tautomeric equilibria of a novel Schiff base L derived from pyridoxal (PL) and o-phenylenediamine by using the density functional method B3LYP with basis sets 6-31 G(d,p), 6-31++G(d,p), 6-311 G(d,p) and 6-311++G(d,p). The optimized geometrical parameters obtained by B3LYP/6-31 G(d,p) method showed the best agreement with the experimental values. Tautomeric stability study of L inferred that the enolimine form is more stable than its ketoenamine form in both gas phase and solution. However, protonation of the pyridoxal nitrogen atom (LH) have accelerated the formation of ketoenamine form, and therefore, both ketoenamine and enolimine forms could be present in acidic media.     

Ab initio and DFT study of the inner mechanism and dynamic stereochemistry of electrophilic addition reaction of bromine to bisbenzotetracyclo[6.2.2.23,6.02,7]tetradeca-4,9,11,13-tetraene

The inner mechanism and dynamic stereochemistry of electrophilic addition of bromine to bisbenzotetracyclo[6.2.2.2(3,6).0(2,7)]tetradeca-4,9,11,13-tetraene(BBTT) molecule have been investigated by the methods of quantum chemistry. The structure of the BBTT molecule has been studied by ab initio and DFT/B3LYP methods using the 6-31G(d) and 6-311G(d) basis sets. The double bonds of BBTT molecule are endo-pyramidalized. The structure and stability of the cationic intermediates and products of the addition reaction have been investigated by HF/6-311G(d), HF/6-311G(d,p), B3LYP/6-311G(d) and B3LYP/6-311++G(2d,p)//B3LYP/6-311G(d) methods. The bridged bromonium cation isomerized into the more stable nonclassical delocalized N- and U-type cations and the difference between the stability of these cations is small. For the determination of the direction of addition reaction and the stereochemistry of the products, the stability of nonclassical delocalized N- and U-type ions and the structure of their cationic centres play a vital role. Since the cationic centre of the N-type ion is in interaction with the benzene ring from the exo face, the nucleofilic attackof the bromide anion to this centre occurs from the endo face and the exo,endo-isomer of the N-type product is obtained. The attack of bromide anion, towards the cationic centre of U-type ion from the endo face is sterically hindered by the hydrogen atom therefore the attack occurs from the exo face, which interacts with the benzene ring and the more stable exo,exo-isomer of U-type product is formed. Although, the U-type cation was 2.232 kcal mol(-1) more stable than the N-type cation, the U-type product was 0.587 kcal mol(-1) less stable than the N-type product.     

Molecular structure,vibrational spectra and HOMO,LUMO analysis of 4-piperidone by density functional theory and ab initio Hartree–Fock calculations

Vibrational frequencies and geometrical parameters of 4-piperidone (4-PID) in the ground state have been calculated by using the Hartree–Fock (HF) and density functional methods (B3LYP) with 6-311++G(d,p) and 6-311+G(3df,2p) basis sets. These methods are proposed as a tool to be applied in the structural characterisation of 4-PID (C₅H₉NO). The title molecule has C _s point group symmetry, thus providing useful support in the interpretation of experimental IR and Raman data. The DFT-B3LYP/6-311+G(3df,2p) calculations have been found more reliable than the ab initio HF/6-311++G(d,p) calculations for the vibrational study of 4-PID. The calculated highest occupied molecular orbital and lowest unoccupied molecular orbital energies show that charge transfer occurs within the molecule. The theoretical spectrograms for FT-IR and FT-Raman spectra of the title molecule have been constructed.     

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.     

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.     

Tautomeric energetics of xanthine oxidase substrates: xanthine, 2-oxo-6-methylpurine, and lumazine

The stability of the tautomers of each of the three important substrates of xanthine oxidase, xanthine, 2-oxo-6-methylpurine, and lumazine, was examined by quantum mechanical calculations. The geometries of these tautomers were optimized at the AM1, Hartree-Fock (HF/6-31G), and hybrid Hartree-Fock/density functional theory (B3LYP/6-31G(d)) levels of theory. The single point energies of some of the more stable tautomers for each of the substrates were calculated at the B3LYP/6-311 +G(2d,p) level of theory. The Conductor Polarized Continuum Model (CPCM) was used to evaluate the solvent effects on the relative stabilities of these tautomers. The calculations clearly identify the lowest energy tautomeric form for xanthine and lumazine. On the other hand, there appear to be three tautomers for 2-oxo-6-methylpurine, with only minor energetic differences in vacuo. In water, however, only one of them predominates. The lowest energy tautomers presumably represent the predominant tautomeric forms at the molybdenum center of xanthine oxidase during catalysis. Implications of these computational results are discussed in the context of enzyme catalysis.     

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.     

An assessment to evaluate the validity of different methods for the description of some corrosion inhibitors

New research and development efforts using computational chemistry in studying an assessment of the validity of different quantum chemical methods to describe the molecular and electronic structures of some corrosion inhibitors were introduced. The standard and the highly accurate CCSD method with 6-311++G(d,p), ab initio calculations using the HF/6-31G++(d,p) and MP2 with 6-311G(d,p), 6-31++G(d,p), and 6-311++G(2df,p) methods as well as DFT method at the B3LYP, BP86, B3LYP*, M06L, and M062x/6-31G++(d,p) basis set level were performed on some triazole derivatives and sulfur containing compounds used as corrosion inhibitors. Quantum chemical parameters, such as the energy of the highest occupied molecular orbital energy (E_HOMO), the energy of the lowest unoccupied molecular orbital energy (E_LUMO), energy gap (ΔE), dipole moment (μ), sum of total negative charges (TNC), chemical potential (Pi), electronegativity (χ), hardness (η), softness (σ), local softness (s), Fukui functions (f ⁺,f ^?), electrophilicity (ω), the total energy change (?E_T) and the solvation energy (S.E), were calculated. Furthermore, the accuracy and the applicability of these methods were estimated relative to the highest accuracy and standard CCSD with 6-311++G(d,p) method. Good correlations between the quantum chemical parameters and the corresponding inhibition efficiency (IE%) were found.     

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.     

Excited state intramolecular proton transfer in 3-hydroxy flavone and 5-hydroxy flavone: A DFT based comparative study

Potential energy (PE) curves for the intramolecular proton transfer in the ground (GSIPT) and excited (ESIPT) states of 3-hydroxy-flavone (3HF) and 5-hydroxy-flavone (5HF) were studied using DFT/B3LYP (6-31G (d,p)) and TD-DFT/B3LYP (6-31G (d,p)) level of theory respectively. Our calculations suggest the non-viability of ground state intramolecular proton transfer for both the compounds. Calculated PE curves of 3HF for the ground and excited singlet states proton transfer process explain its four state laser diagram. Excited states PE calculations support the ESIPT process to both 5HF and 3HF. The difference in ESIPT emission process of 3HF and 5HF have been explained in terms of HOMO and LUMO electron distribution of the enol and keto tautomer of these two compounds.     

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.     

Comparative theoretical study of the UV/Vis absorption spectra of styrylpyridine compounds using TD-DFT calculations

This study examined absorption properties of 2-styrylpyridine, trans-2-(m-cyanostyryl)pyridine, trans-2-[3-methyl-(m-cyanostyryl)]pyridine, and trans-4-(m-cyanostyryl)pyridine compounds based on theoretical UV/Vis spectra, with comparisons between time-dependent density functional theory (TD-DFT) using B3LYP, PBE0, and LC-ωPBE functionals. Basis sets 6–31G(d), 6–31G(d,p), 6–31+G(d,p), and 6–311+G(d,p) were tested to compare molecular orbital energy values, gap energies, and maxima absorption wavelengths. UV/Vis spectra were calculated from fully optimized geometry in B3LYP/6–311+G(d,p) in gas phase and using the IEFPCM model. B3LYP/6–311+G(d,p) provided the most stable form, a planar structure with parameters close to 2-styrylpyridine X-ray data. Isomeric structures were evaluated by full geometry optimization using the same theory level. Similar energetic values were found: ～4.5 kJ?mol^?1 for 2-styrylpyridine and ～1 kJ?mol^?1 for derivative compound isomers. The 2-styrylpyridine isomeric structure differed at the pyridine group N-atom position; structures considered for the other compounds had the cyano group attached to the phenyl ring m-position equivalent. The energy difference was almost negligible between m-cyano-substituted molecules, but high energy barriers existed for cyano-substituted phenyl ring torsion. TD-DFT appeared to be robust and accurate approach. The B3LYP functional with the 6–31G(d) basis set produced the most reliable λ_max values, with mean errors of 0.5 and 12 nm respect to experimental values, in gas and solution, respectively. The present data describes effects on the λ_max changes in the UV/Vis absorption spectra of the electron acceptor cyano substituent on the phenyl ring, the electron donor methyl substituent, and the N-atom position on the electron acceptor pyridine ring, causing slight changes respect to the 2-styrylpyridine title compound.     

Cα torsion angles as a flexible criterion to extract secrets from a molecular dynamics simulation

A multipolar, polarizable electrostatic method for future use in a novel force field is described. Quantum Chemical Topology (QCT) is used to partition the electron density of a chemical system into atoms, then the machine learning method Kriging is used to build models that relate the multipole moments of the atoms to the positions of their surrounding nuclei. The pilot system serine is used to study both the influence of the level of theory and the set of data generator methods used. The latter consists of: (i) sampling of protein structures deposited in the Protein Data Bank (PDB), or (ii) normal mode distortion along either (a) Cartesian coordinates, or (b) redundant internal coordinates. Wavefunctions for the sampled geometries were obtained at the HF/6-31G(d,p), B3LYP/apc-1, and MP2/cc-pVDZ levels of theory, prior to calculation of the atomic multipole moments by volume integration. The average absolute error (over an independent test set of conformations) in the total atom-atom electrostatic interaction energy of serine, using Kriging models built with the three data generator methods is 11.3 kJ mol^-1 (PDB), 8.2 kJ mol^-1 (Cartesian distortion), and 10.1 kJ mol^-1 (redundant internal distortion) at the HF/6-31G(d,p) level. At the B3LYP/apc-1 level, the respective errors are 7.7 kJ mol^-1, 6.7 kJ mol^-1, and 4.9 kJmol^-1, while at the MP2/cc-pVDZ level they are 6.5 kJ mol^-1, 5.3 kJ mol^-1, and 4.0 kJmol^-1. The ranges of geometries generated by the redundant internal coordinate distortion and by extraction from the PDB are much wider than the range generated by Cartesian distortion. The atomic multipole moment and electrostatic interaction energy predictions for the B3LYP/apc-1 and MP2/cc-pVDZ levels are similar, and both are better than the corresponding predictions at the HF/6-31G(d,p) level.     

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.     

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.