Predicting the NMR spectra of nucleotides by DFT calculations: cyclic uridine monophosphate

We present an experimental and quantum chemical NMR study of the mononucleotide cyclic uridine monophosphate in water. Spectral parameters ((1)H and (13)C chemical shifts and (1)H--(1)H, (13)C--(1)H, (31)P--(13)C and (31)P--(1)H spin-spin coupling constants) have been carefully obtained experimentally and calculated using DFT methods including the solvent effect and the conformational flexibility of the solute. This study confirms that the (1)H and (13)C spectra of polar, flexible molecules in aqueous solution can be predicted with a high level of accuracy, comparable to that obtained for less complex systems.     

Calculated and experimental NMR chemical shifts of p-menthane-3,9-diols. A combination of molecular dynamics and quantum mechanics to determine the structure and the solvent effects

NMR chemical shifts have been experimentally measured and theoretically estimated for all the carbon atoms of (1R,3S,4S,8S)-p-menthane-3,9-diol in chloroform solution. Theoretical estimations were performed using a combination of molecular dynamics simulations and quantum mechanical calculations. Molecular dynamics simulations were used to obtain the most populated conformations of the (1R,3S:4S,8S)-p-menthane-3,9-diol as well as the distribution of the solvent molecules around it. Quantum mechanical calculations of NMR chemical shifts were performed on the most relevant conformations employing the GIAO-DFT formalism. A special emphasis was put in evaluating the effects of the surrounding solvent molecules. For this purpose, supermolecule calculations were performed on complexes constituted by the solute and n chloroform molecules, where n ranges from 3 to 16. An excellent agreement with experimental data has been obtained following this computational strategy.     

Understanding sterol-membrane interactions part I: Hartree-Fock versus DFT calculations of 13C and 1H NMR isotropic chemical shifts of sterols in solution and analysis of hydrogen-bonding effects

1H and 13C NMR chemical shifts are exquisitely sensitive probes of the local environment of the corresponding nuclei. Ultimately, direct determination of the chemical shifts of sterols in their membrane environment has the potential to reveal their molecular interactions and dynamics, in particular concerning the hydrogen-bonding partners of their OH groups. However, this strategy requires an accurate and efficient means to quantify the influence of the various interactions on chemical shielding. Herein the validity of Hartree-Fock and DFT calculations of the 13C and 1H NMR chemical shifts of cholesterol and ergosterol are compared with one another and with experimental chemical shifts measured in solution at 500 MHz. A computational strategy (definition of basis set, simpler molecular models for the sterols themselves and their molecular complexes) is proposed and compared with experimental data in solution. It is shown in particular that the effects of hydrogen bonding with various functional groups (water as a hydrogen-bond donor and acceptor, acetone) on NMR chemical shifts in CDCl3 solution can be accurately reproduced with this computational approach.     

Quantum chemical and nuclear magnetic resonance spectral studies on molecular properties and electronic structure of berberine and berberrubine

The structural and electronic properties of berberine and berberrubine have been studied extensively using density functional theory (DFT) employing B3LYP exchange correlation. The geometries of these molecules have been fully optimized at the B3LYP/6-311G** level. The chemical shift of 1H and 13C resonances in NMR spectra of these molecules have been calculated using the gauge invariant atomic model (GIAO) method as implemented in Gaussian 98. One- and two-dimensional HSQC (1H-13C), HMBC (1H-13C) and ROESY (1H-1H) spectra were recorded at 500 MHz for the berberine molecule in D(2)O solution. All proton and carbon resonances were unambiguously assigned, and inter-proton distances obtained from ten observed NOE contacts. A restrained molecular dynamics (RMD) approach was used to get the optimized solution structure of berberine. The structure of berberine and berberrubine molecules was also obtained using the ROESY data available in literature. Comparison of the calculated NMR chemical shifts with the experimental values revealed that DFT methods produce very good results for both proton and carbon chemical shifts. The importance of the basis sets to the calculated NMR parameters is discussed. It has been found that calculated structure and chemical shifts in the gas phase predicted with B3LYP/6-311G** are in very good agreement with the present experimental data and the measured values reported earlier.     

Fragment density functional theory calculation of NMR chemical shifts for proteins with implicit solvation

Fragment density functional theory (DFT) calculation of NMR chemical shifts for several proteins (Trp-cage, Pin1 WW domain, the third IgG-binding domain of Protein G (GB3) and human ubiquitin) has been carried out. The present study is based on a recently developed automatic fragmentation quantum mechanics/molecular mechanics (AF-QM/MM) approach but the solvent effects are included by using the PB (Poisson-Boltzmann) model. Our calculated chemical shifts of (1)H and (13)C for these four proteins are in excellent agreement with experimentally measured values and represent clear improvement over that from the gas phase calculation. However, although the inclusion of the solvent effect also improves the computed chemical shifts of (15)N, the results do not agree with experimental values as well as (1)H and (13)C. Our study also demonstrates that AF-QM/MM calculated results accurately reproduce the separation of α-helical and β-sheet chemical shifts for (13)C(α) atoms in proteins, and using the (1)H chemical shift to discriminate the native structure of proteins from decoys is quite remarkable.     

Crystallographic and Dynamic Aspects of Solid‐State NMR Calibration Compounds: Towards ab Initio NMR Crystallography

The excellent results of dispersion‐corrected density functional theory (DFT‐D) calculations for static systems have been well established over the past decade. The introduction of dynamics into DFT‐D calculations is a target, especially for the field of molecular NMR crystallography. Four ¹³C ss‐NMR calibration compounds are investigated by single‐crystal X‐ray diffraction, molecular dynamics and DFT‐D calculations. The crystal structure of 3‐methylglutaric acid is reported. The rotator phases of adamantane and hexamethylbenzene at room temperature are successfully reproduced in the molecular dynamics simulations. The calculated ¹³C chemical shifts of these compounds are in excellent agreement with experiment, with a root‐mean‐square deviation of 2.0 ppm. It is confirmed that a combination of classical molecular dynamics and DFT‐D chemical shift calculation improves the accuracy of calculated chemical shifts.     

A study on quantum chemical calculations of 3-, 4-nitrobenzaldehyde oximes

The molecular geometry, vibrational frequencies, 1H and 13C NMR chemical shifts, UV-vis spectra, HOMO-LUMO analyses, molecular electrostatic potentials (MEPs), , thermodynamic properties and atomic charges of 3- and 4-Nitrobenzaldehyde oxime (C7H6N2O3) molecules have been investigated by using Hartree-Fock (HF) and density functional theory (DFT/B3LYP) methods with the 6-311++G(d, p) basis set. The calculated optimized geometric parameters (bond lengths and bond angles), the vibrational frequencies calculated and 13C and 1H NMR chemical shifts values for the mentioned compounds are in a very good agreement with the experimental data. Furthermore, the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) have been simulated and the transition states, energy band gaps and molecular electrostatic potential (MEP) maps for each oxime compound have been determined. Additionally, we also report the infrared intensities and Raman activities for the compounds under study.     

Computing the NMR spectrum of a bulk ionic liquid phase by QM/MM methods

The dependence of (1)H and (13)C NMR chemical shifts of 1-butyl-3-methylimidazolium ([bmim])-based room-temperature ionic liquids on the counteranion ([BF(4)], [MeSO(4)]) is investigated experimentally and computationally. The local structure of the ionic liquids is investigated by means of DFT calculations of the structure of ion pairs and molecular dynamics simulations. Clusters extracted from the simulation runs are used to calculate (1)H and (13)C chemical shifts by means of QM/MM methods with various partition schemes. Proton H2 of the imidazolium ring is the most sensitive to the counteranion; its chemical shift is strongly dependent on subtle details of the arrangement of the two closest anions. It is shown that a correct spacing of signals can be attained by including the two anions closest to C2 and H2 in the QM layer.     

Intramolecular hydrogen-bonding interactions in 2-nitrosophenol and nitrosonaphthols: ab initio, density functional, and nuclear magnetic resonance theoretical study

Intramolecular hydrogen bonding (IHB) interactions and molecular structures of 2-nitrosophenol, nitrosonaphthols, and their quinone-monooxime tautomers were investigated at ab initio and density functional theory (DFT) levels. The geometry optimization of the structures studied was performed without any geometrical restrictions. Possible conformations with different types of the IHB of the tautomers were considered to understand the nature of the HB among these conformers. The effect of solvent on hydrogen bond energies, conformational equilibria, and tautomerism in aqueous solution were studied. Natural bond orbital analysis was performed to study the IHB in the gaseous phase and in aqueous medium. The NMR 1H, 13C, 15N, and 17O chemical shifts in the gaseous phase and in solution for the studied compounds were calculated using the gauge-including atomic orbitals approach implemented in the Gaussian 03 program package. The optimized geometrical parameters and 1H NMR chemical shifts are in good agreement with previous theoretical and experimental data.     

Chemical shifts in nucleic acids studied by density functional theory calculations and comparison with experiment

NMR chemical shifts are highly sensitive probes of local molecular conformation and environment and form an important source of structural information. In this study, the relationship between the NMR chemical shifts of nucleic acids and the glycosidic torsion angle, χ, has been investigated for the two commonly occurring sugar conformations. We have calculated by means of DFT the chemical shifts of all atoms in the eight DNA and RNA mono-nucleosides as a function of these two variables. From the DFT calculations, structures and potential energy surfaces were determined by using constrained geometry optimizations at the BP86/TZ2P level of theory. The NMR parameters were subsequently calculated by single-point calculations at the SAOP/TZ2P level of theory. Comparison of the (1) H and (13) C?NMR shifts calculated for the mono-nucleosides with the shifts determined by NMR spectroscopy for nucleic acids demonstrates that the theoretical shifts are valuable for the characterization of nucleic acid conformation. For example, a clear distinction can be made between χ angles in the anti and syn domains. Furthermore, a quantitative determination of the χ angle in the syn domain is possible, in particular when (13) C and (1) H chemical shift data are combined. The approximate linear dependence of the C1' shift on the χ angle in the anti domain provides a good estimate of the angle in this region. It is also possible to derive the sugar conformation from the chemical shift information. The DFT calculations reported herein were performed on mono-nucleosides, but examples are also provided to estimate intramolecularly induced shifts as a result of hydrogen bonding, polarization effects, or ring-current effects.     

Spectroscopic, electronic structure and natural bond orbital analysis of o-fluoronitrobenzene and p-fluoronitrobenzene: a comparative study

Experimental FTIR, FT-Raman and FT-NMR spectroscopic studies of o-fluoronitrobenzene and p-fluoronitrobenzene have been carried out. A detailed quantum chemical calculations have been performed using DFT/B3LYP method with 6-311++G** and 6-31G** basis sets. Complete vibrational analyses of the compounds were performed. The temperature dependence of thermodynamic properties has been analysed. The atomic charges, electronic exchange interaction and charge delocalisation of the molecule have been performed by natural bond orbital (NBO) analysis. Molecular electrostatic surface potential (MESP), total electron density distribution and frontier molecular orbitals (FMOs) are constructed at B3LYP/6-311++G** level to understand the electronic properties. The charge density distribution and site of chemical reactivity of the molecules have been obtained by mapping electron density isosurface with electrostatic potential surfaces (ESP). The electronic properties, HOMO and LUMO energies were measured by time-dependent TD-DFT approach. (1)H and (13)C NMR spectra were recorded and (1)H and (13)C nuclear magnetic resonance chemical shifts of the molecule were calculated. The (1)H and (13)C nuclear magnetic resonance (NMR) chemical shifts of the molecules in chloroform solvent and in gas phase were calculated by using the Gauge-Independent Atomic Orbital (GIAO) method and are found to be in good agreement with experimental values. The theoretical parameters obtained at B3LYP levels have been compared with the experimental values.     

Probing NMR parameters, structure and dynamics of 5-nitroimidazole derivatives. Density functional study of prototypical radiosensitizers

The 15N chemical shifts of metronidazole (1), secnidazole (2), nimorazole (3) and tinidazole (4), radiosensitizers based on the 5-nitroimidazole motif, are reported. A detailed computational study of 1 is presented, calling special attention to the performance of various theoretical methods in reproducing the 13C and 15N data observed in solution. The most sophisticated approach involves density functional-based Car-Parrinello molecular dynamics simulations (CPMD) of 1 in aqueous solution (BP86 level) and averaging chemical shifts over snapshots from the trajectory. In the NMR calculations for these snapshots (performed at the B3LYP level), a small number of discrete water molecules are retained, and the remaining bulk solution effects are included via a polarizable continuum model (PCM). A similarly good accord with experiment is obtained from much less involved, static geometry optimization and NMR computation of pristine 1 employing a PCM approach. Solvent effects on delta(15N), which are of the order of up to 20 ppm, are not due to changes in geometric parameters upon solvation, but arise from the direct response of the electronic wavefunction to the presence of the solvent, which can be represented by discrete molecules and/or the dielectric bulk.     

Solution and solid-state effects on NMR chemical shifts in sesquiterpene lactones: NMR, X-ray, and theoretical methods

Selected guaianolide type sesquiterpene lactones were studied combining solution and solid-state NMR spectroscopy with theoretical calculations of the chemical shifts in both environments and with the X-ray data. The experimental (1)H and (13)C chemical shifts in solution were successfully reproduced by theoretical calculations (with the GIAO method and DFT B3LYP 6-31++G**) after geometry optimization (DFT B3LYP 6-31 G**) in vacuum. The GIPAW method was used for calculations of solid-state (13)C chemical shifts. The studied cases involved two polymorphs of helenalin, two pseudopolymorphs of 6α-hydroxydihydro-aromaticin and two cases of multiple asymmetric units in crystals: one in which the symmetry-independent molecules were connected by a series of hydrogen bonds (geigerinin) and the other in which the symmetry-independent molecules, deprived of any specific intermolecular interactions, differed in the conformation of the side chain (badkhysin). Geometrically different molecules present in the crystal lattices could be easily distinguished in the solid-state NMR spectra. Moreover, the experimental differences in the (13)C chemical shifts corresponding to nuclei in different polymorphs or in geometrically different molecules were nicely reproduced with the GIPAW calculations.     

The impact of the pi-electron conjugation on (15)N, (13)C and (1)H NMR chemical shifts in push-pull benzothiazolium salts. Experimental and theoretical study

The (15)N as well as (13)C and (1)H chemical shifts of eight push-pull benzothiazolium iodides with various pi-conjugated chains between dimethylamino group and benzothiazolium moiety have been determined by NMR spectroscopy at the natural-abundance level of all nuclei in DMSO-d(6) solution. In general, the quaternary benzothiazolium nitrogen is more shielded [delta((15)N-3) vary between - 241.3 and - 201.9 ppm] with respect to parent 3-methylbenzothiazolium iodide [delta((15)N-3) = - 183.8 ppm], depending on the length and constitution of the pi-conjugated bridge. A larger variation in (15)N chemical shifts is observed on dimethylamino nitrogen, which covers the range of - 323.3 to - 257.2 ppm. The effect of pi-conjugation degree has a less pronounced influence on (13)C and (1)H chemical shifts. Experimental data are interpreted by means of density functional theory (DFT) calculations. Reasonable agreement between theoretical and experimental (15)N NMR chemical shifts was found, particularly when performing calculations with hybrid exchange-correlation functionals. A better accord with experiment is achieved by utilizing a polarizable continuum model (PCM) along with an explicit treatment of hydrogen-bonding between the solute and the water present in dimethylsulfoxide (DMSO). Finally, (13)C and (1)H NMR spectra were computed and analysed in order to compare them with available experimental data.     

Spectroscopic and theoretical study of 2-acetylphenyl-2-naphthoate

Mid-, far-infrared and Raman vibrational spectra of 2-acetylphenyl-2-naphthoate have been measured at room and low temperatures. The molecule was also analyzed by means of ab initio calculations. The conformational space has been scanned using molecular dynamics and complemented with functional density calculations that optimize the geometry of the lowest energy conformers 2-acetylphenyl-2-naphthoate as obtained in the simulations. The vibrational frequencies and the (1)H and (13)C NMR chemical shifts were assigned using functional density calculations. The theoretical chemical shift values were compared with the experimental ones. The molecular electrostatic potential maps were obtained and analyzed.     

Thermal and solvent effects on the NMR and UV parameters of some bioreductive drugs

15N NMR chemical shifts and n-->pi* electronic transition energy for metronidazole (1) has been calculated and compared with experimental data. A detailed computational study of 1 is presented, with special attention to the performance of various theoretical methods for reproducing spectroscopic parameters in solution. The most sophisticated approach involves density functional based on the Car-Parrinello molecular dynamics simulations of 1 in aqueous solution (BP86 level) and averaging chemical shifts and deltaE(n-->pi*) over snapshots from the trajectory. In the NMR and UV calculations for these snapshots (performed at the B3LYP level), a small number of discrete water molecules are retained, and the remaining bulk solution effects are included via a polarizable continuum model (PCM). A good agreement with experiment is also obtained using static geometry optimization and NMR computation of pristine 1 employing a PCM approach. Further theoretical predictions are also reported for 17O NMR and deltaE(n-->pi*) of three hydroxycinnamic acid derivatives, which suggest that it is essential to incorporate the dynamics and solvent effects for NMR and UV calculations in the condensed phase.     

Computational studies of 13C NMR chemical shifts of saccharides

The (13)C NMR chemical shifts for alpha-D-lyxofuranose, alpha-D-lyxopyranose (1)C(4), alpha-D-lyxopyranose (4)C(1), alpha-D-glucopyranose (4)C(1), and alpha-D-glucofuranose have been studied at ab initio and density-functional theory levels using TZVP quality basis set. The methods were tested by calculating the nuclear magnetic shieldings for tetramethylsilane (TMS) at different levels of theory using large basis sets. Test calculations on the monosaccharides showed B3LYP(TZVP) and BP86(TZVP) to be cost-efficient levels of theory for calculation of NMR chemical shifts of carbohydrates. The accuracy of the molecular structures and chemical shifts calculated at the B3LYP(TZVP) level is comparable to those obtained at the MP2(TZVP) level. Solvent effects were considered by surrounding the saccharides by water molecules and also by employing a continuum solvent model. None of the applied methods to consider solvent effects was successful. The B3LYP(TZVP) and MP2(TZVP)(13)C NMR chemical shift calculations yielded without solvent and rovibrational corrections an average deviation of 5.4 ppm and 5.0 ppm between calculated and measured shifts. A closer agreement between calculated and measured chemical shifts can be obtained by using a reference compound that is structurally reminiscent of saccharides such as neat methanol. An accurate shielding reference for carbohydrates can be constructed by adding an empirical constant shift to the calculated chemical shifts, deduced from comparisons of B3LYP(TZVP) or BP86(TZVP) and measured chemical shifts of monosaccharides. The systematic deviation of about 3 ppm for O(1)H chemical shifts can be designed to hydrogen bonding, whereas solvent effects on the (1)H NMR chemical shifts of C(1)H were found to be small. At the B3LYP(TZVP) level, the barrier for the torsional motion of the hydroxyl group at C(6) in alpha-D-glucofuranose was calculated to 7.5 kcal mol(-1). The torsional displacement was found to introduce large changes of up to 10 ppm to the (13)C NMR chemical shifts yielding uncertainties of about +/-2 ppm in the chemical shifts.     

Thermal and solvent effects on NMR indirect spin-spin coupling constants of a prototypical Chagas disease drug

NMR J-couplings across hydrogen bonds reflect the static and dynamic character of hydrogen bonding. They are affected by thermal and solvent effects and can therefore be used to probe such effects. We have applied density functional theory (DFT) to compute the NMR (n)J(N,H) scalar couplings of a prototypical Chagas disease drug (metronidazole). The calculations were done for the molecule in vacuo, in microsolvated cluster models with one or few water molecules, in snapshots obtained from molecular dynamics simulations with explicit water solvent, and in a polarizable dielectric continuum. Hyperconjugative and electrostatic effects on spin-spin coupling constants were assessed through DFT calculations using natural bond orbital (NBO) analysis and atoms in molecules (AIM) theory. In the calculations with explicit solvent molecules, special attention was given to the nature of the hydrogen bonds formed with the solvent molecules. The results highlight the importance of properly incorporating thermal and solvent effects into NMR calculations in the condensed phase.     

Computational NMR spectroscopy of organoarsenicals and the natural polyarsenic compound arsenicin A

The (1)H and (13)C NMR chemical shifts and coupling constants of a series of organoarsenic compounds were calculated with DFT methods and compared with available experimental spectra. We show that non-relativistic methods successfully model the NMR spectra of these molecules; relativistic spin-orbit effects are small but appreciable for (13)C shifts, and their inclusion is beneficial. Application of the same methods of calculation to the intriguing natural polyarsenic compound arsenicin A allowed several viable alternative structures to be ruled out and thereby confirmed the previously suggested adamantane-like structure of arsenicin A. These results not only reinforce the known predictive power of DFT NMR calculations, but also open the way for the investigation of other naturally occurring molecules with unusual structures outside the scope of empirical methods.