Chemical Shift Tensors Research Articles

Density Functional Theory Study of Interaction between Ibuprofen and Alginic Acid for Targeted Drug Delivery

Abstract:: The development of density functional theory has led to the consideration of computational chemistry in the design and development of interactions of new drugs in the gas phase with nanocarriers. In the present study, the interaction of ibuprofen with alginic acid (as a nanocarrier) has been investigated using density functional theory (DFT) in the gas phase (M06-2X/6-31+G*). A study on the effects of ibuprofen’s interaction with the compounds present in alginic acid has been conducted, focusing on the electronic properties, the chemical shift tensors, and the natural bond orbital. Based on the results of UV spectra, the compound 6-thioguanine has been found to be changed into an alginic acid/ibuprofen complex. The quantum theory of atoms in molecules showed the interaction of ibuprofen to be mainly driven by non-covalent bonds with alginic acid during complex formation. A hydrogen bond has been found to be formed between the oxygen atoms of alginic acid and ibuprofen's hydrogen atoms. Consequently, alginic acid has been used for delivering ibuprofen to diseased cells.

Electrostatic Surface Potentials and Chalcogen-Bonding Motifs of Substituted 2,1,3-Benzoselenadiazoles Probed via 77Se Solid-State NMR Spectroscopy.

Chalcogen bonds (ChB) are moderately strong, directional, and specific non-covalent interactions that have garnered substantial interest over the last decades. Specifically, the presence of two σ-holes offers great potential for crystal engineering, catalysis, biochemistry, and molecular sensing. However, ChB applications are currently hampered by a lack of methods to characterize and control chalcogen bonds. Here, we report on the influence of various substituents (halogens, cyano, and methyl groups) on the observed self-complementary ChB networks of 2,1,3-benzoselenadiazoles. From molecular electrostatic potential calculations, we show that the electrostatic surface potentials (ESP) of the σ-holes on selenium are largely influenced by the electron-withdrawing character of these substituents. Structural analyses via X-ray diffraction reveal a variety of ChB geometries and binding modes that are rationalized via the computed ESP maps, although the structure of 5,6-dimethyl-2,1,3-benzoselenadiazole also demonstrates the influence of steric interactions. 77Se solid-state magic-angle spinning NMR spectroscopy, in particular the analysis of the selenium chemical shift tensors, is found to be an effective probe able to characterize both structural and electrostatic features of these self-complementary ChB systems. We find a positive correlation between the value of the ESP maxima at the σ-holes and the experimentally measured 77Se isotropic chemical shift, while the skew of the chemical shift tensor is established as a metric which is reflective of the ChB binding motif.

Fingerprints of Chalcogen Bonding Revealed Through 77Se-NMR.

77Se-NMR is used to characterise several chalcogen bonded complexes of derivatives of the organoselenium drug ebselen, exploring a range of electron demand. NMR titration experiments support the intuitive understanding that chalcogen bond donors bearing more electron withdrawing substituents give rise stronger chalcogen bonds. The chemical shift of the selenium nucleus is also shown to move upfield as it participates in a chalcogen bond. Solid-state NMR is used to explore chalcogen bonding in co-crystals. Due to the lack of molecular reorientation on the NMR timescale in the solid state, the shape of the chemical shift tensor can be determined using this technique. A range of co-crystals are shown to have extremely large chemical shift anisotropy, which suggests a strongly anisotropic electron density distribution around the selenium atom. A single crystal NMR experiment was conducted using one of the co-crystals, affording the absolute orientation of the chemical shift tensor within the crystal. This showed that the selenium nucleus is strongly shielded in the direction of the chalcogen bond (due to the approach of the lone pair of the Lewis base), and strongly deshielded in the perpendicular direction. The orientation of the deshielded axis is consistent with the presence of a second σ-hole which is not participating in a chalcogen bond, showing the profound effect of electron density anisotropy on the chemical shift.

Characterization of the Pb Coordination Environment and Its Connectivity in Lead Silicate Glasses: Results from 2D 207Pb NMR Spectroscopy.

The Pb-O coordination environment in binary (PbO)x(SiO2)100-x glasses with 30 ≤ x ≤ 70 is probed by using two-dimensional 207Pb nuclear magnetic resonance (NMR) isotropic-anisotropic correlation spectroscopy. The isotropic 207Pb NMR spectra show little composition-dependent evolution of the Pb-O nearest-neighbor coordination environment. The systematic variation of the chemical shift tensor parameters offers a unique insight into their local site symmetry and suggests the presence of pyramidal PbO3 and PbO4 sites with sterically active electron lone pairs and with Pb-O bond lengths ranging between 0.23 and 0.25 nm. The PbO3/PbO4 ratio shows a small but monotonic increase from ∼70:30 to 80:20 as the PbO content increases from 30 to 70 mol %. When taken together, the isotropic and anisotropic 207Pb NMR spectra suggest that the majority of the PbOn (3 ≤ n ≤ 4) pyramids in these glasses are connected to the SiO4 tetrahedra via Pb-O-Si linkages. A significant fraction of Pb-O-Pb linkages, where the oxygen is linked only to Pb atoms, appears only in glasses with PbO ≥ 60 mol %. These oxygen atoms appear to be corner-shared between the PbOn pyramids in the structure, and no evidence for edge-sharing between these pyramids is observed in this composition range. We hypothesize that a substantial fraction of the constituent PbOn pyramids start to participate in edge-sharing only at higher PbO contents (>70 mol %), which diminishes the glass-forming ability of the network. This work illustrates the potential of isotropic-anisotropic correlation NMR spectroscopy in structural studies involving nuclides with large chemical shift ranges and anisotropy.

Fluorine labelling for in situ 19F NMR in oriented systems.

The focus of this project is to take advantage of the large NMR chemical shift anisotropy of 19F to determine the orientation of fluorine labeled biomolecules in situ in oriented biological systems such as muscle. The difficulty with a single fluorine atom is that the orientation determined from a chemical shift is not singlevalued in the case of a fully anisotropic chemical shift tensor. The utility of a labeling approach with two fluorine labels in a fixed molecular framework where one of the labels has an axially symmetric chemical shift anisotropy such as a CF3 group and the other has a fully asymmetric chemical shift anisotropy such as 5-fluorotryptophan is evaluated. The result is that the orientation of the label can be determined straightforwardly from a single one-dimensional 19F NMR spectrum. The potential applications are widespread and not limited to biological applications.

The Scope of the Applicability of Non-relativistic DFT Calculations of NMR Chemical Shifts in Pyridine-Metal Complexes for Applied Applications.

Heavy metals are toxic, but it is impossible to stop using them. Considering the variety of molecular systems in which they can be present, the multicomponent nature and disorder of the structure of such systems, one of the most effective methods for studying them is NMR spectroscopy. This determines the need to calculate NMR chemical shifts for expected model systems. For elements beyond the third row of the periodic table, corrections for relativistic effects are necessary when calculating NMR parameters. Such corrections may be necessary even for light atoms due to the shielding effect of a neighboring heavy atom. This work examines the extent to which non-relativistic DFT calculations are able to reproduce experimental 15N and 113Cd NMR chemical shift tensors in pyridine-metal coordination complexes. It is shown that while for the calculation of 15N NMR chemical shift tensors there is no real need to consider relativistic corrections, for 113Cd, on the contrary, none of the tested calculation methods could reproduce the experimentally obtained tensor to any extent correctly.

Distinguishing between COOH, COO- , and hydrogen disordered COOH sites in solids with 13 C chemical shift anisotropy and T1 measurements.

Since 1993, it has been known that 13 C chemical shift tensor (i.e., δ11 , δ22 , and δ33 ) provides information sufficient to distinguish between COOH and COO- sites. Herein, four previously unreported metrics are proposed for differentiating COOH/COO- moieties. A new relationship is also introduced that correlates the asymmetry (i.e., δ11 -δ22 ) of COOH sites to the proximity of hydrogen bond donating partners within 2.6Å with high accuracy (±0.05Å). Conversely, a limitation to all proposed metrics is that they fail to distinguish between COO- and hydrogen disordered COOH sites. To reconcile this omission, a new approach is proposed based on T1 measurements of both 1 H and 13 C. The 13 C T1 values are particularly sensitive with the T1 for hydrogen disordered COOH moieties found to be nearly six times smaller than T1 's from COO- sites.

Carbon-13 chemical shift tensor measurements for nitrogen-dense compounds.

This paper reports the principal values of the 13 C chemical shift tensors for five nitrogen-dense compounds (i.e., cytosine, uracil, imidazole, guanidine hydrochloride, and aminoguanidine hydrochloride). Although these are all fundamentally important compounds, the majority do not have 13 C chemical shift tensors reported in the literature. The chemical shift tensors are obtained from 1 H→13 C cross-polarization magic-angle spinning (CP/MAS) experiments that were conducted at a high field of 18.8T to suppress the effects of 14 N-13 C residual dipolar coupling. Quantum chemical calculations using density functional theory are used to obtain the 13 C magnetic shielding tensors for these compounds. The best agreement with experiment arises from calculations using the hybrid functional PBE0 or the double-hybrid functional PBE0-DH, along with the triple-zeta basis sets TZ2P or pc-3, respectively, and intermolecular effects modeled using large clusters of molecules with electrostatic embedding through the COSMO approach. These measurements are part of an ongoing effort to expand the catalog of accurate 13 C chemical shift tensor measurements, with the aim of creating a database that may be useful for benchmarking the accuracy of quantum chemical calculations, developing nuclear magnetic resonance (NMR) crystallography protocols, or aiding in applications involving machine learning or data mining. This work was conducted at the National High Magnetic Field Laboratory as part of a 2-week school for introducing undergraduate students to practical laboratory experience that will prepare them for scientific careers or postgraduate studies.

DFT Study of Interaction between Teriflunomide and β-cyclodextrin

Introduction: This study employs Density Functional Theory (DFT) to investigate the interactions between Teriflunomide and β-cyclodextrin in the gas phase. Method: The non-bonded interaction effects of the Teriflunomide compound with β- cyclodextrin on the chemical shift tensors, electronic properties, and natural charge were also observed. An analysis of the natural bond orbital (NBO) indicated that the molecule β-cyclodextrin as an electron donor functions while Teriflunomide functions as an electron acceptor in the complex β-cyclodextrin/Teriflunomide. Result: The electronic spectra of the Teriflunomide drug and complex β-cyclodextrin/ Teriflunomide were calculated by Time-Dependent Density Functional Theory (TDDFT) to investigate the adsorption effects of the Teriflunomide drug over β-cyclodextrin on maximum wavelength. Conclusion: As a result, the possibility of the use of β-cyclodextrin for Teriflunomide delivery to the diseased cells has been established.

Correction: Chemical shift tensors as probes of chalcogen bonds: solid-state NMR study of telluradiazole-XCN− (X = O, S, Se) salt cocrystals

Correction: Chemical shift tensors as probes of chalcogen bonds: solid-state NMR study of telluradiazole-XCN− (X = O, S, Se) salt cocrystals

Structure and bonding in rhodium coordination compounds: a 103Rh solid-state NMR and relativistic DFT study.

This study demonstrates the application of 103Rh solid-state NMR (SSNMR) spectroscopy to inorganic and organometallic coordination compounds, in combination with relativistic density functional theory (DFT) calculations of 103Rh chemical shift tensors and their analysis with natural bond orbital (NBO) and natural localized molecular orbital (NLMO) protocols, to develop correlations between 103Rh chemical shift tensors, molecular structure, and Rh-ligand bonding. 103Rh is one of the least receptive NMR nuclides, and consequently, there are very few reports in the literature. We introduce robust 103Rh SSNMR protocols for stationary samples, which use the broadband adiabatic inversion-cross polarization (BRAIN-CP) pulse sequence and wideband uniform-rate smooth-truncation (WURST) pulses for excitation, refocusing, and polarization transfer, and demonstrate the acquisition of 103Rh SSNMR spectra of unprecedented signal-to-noise and uniformity. The 103Rh chemical shift tensors determined from these spectra are complemented by NBO/NLMO analyses of contributions of individual orbitals to the 103Rh magnetic shielding tensors to understand their relationship to structure and bonding. Finally, we discuss the potential for these experimental and theoretical protocols for investigating a wide range of materials containing the platinum group elements.

Structural characterization of tin in toothpaste by dynamic nuclear polarization enhanced 119Sn solid-state NMR spectroscopy

Stannous fluoride (SnF2) is an effective fluoride source and antimicrobial agent that is widely used in commercial toothpaste formulations. The antimicrobial activity of SnF2 is partly attributed to the presence of Sn(II) ions. However, it is challenging to directly determine the Sn speciation and oxidation state within commercially available toothpaste products due to the low weight loading of SnF2 (0.454 wt% SnF2, 0.34 wt% Sn) and the amorphous, semi-solid nature of the toothpaste. Here, we show that dynamic nuclear polarization (DNP) enables 119Sn solid-state NMR experiments that can probe the Sn speciation within commercially available toothpaste. Solid-state NMR experiments on SnF2 and SnF4 show that 19F isotropic chemical shift and 119Sn chemical shift anisotropy (CSA) are highly sensitive to the Sn oxidation state. DNP-enhanced 119Sn magic-angle turning (MAT) 2D NMR spectra of toothpastes resolve Sn(II) and Sn(IV) by their 119Sn chemical shift tensor parameters. Fits of DNP-enhanced 1D 1H → 119Sn solid-state NMR spectra allow the populations of Sn(II) and Sn(IV) within the toothpastes to be estimated. This analysis reveals that three of the four commercially available toothpastes contained at least 80% Sn(II), whereas one of the toothpaste contained a significantly higher amount of Sn(IV).

Simulation of oriented NMR spectra: Combining molecular dynamics and chemical shift tensor calculations.

Solid state NMR is widely used to study the orientation and other structural features of proteins and peptides in lipid bilayers. Using data obtained by PISEMA (Polarization Inversion Spin Exchange at Magic Angle) experiments, periodic spectral patterns arise from well-aligned α-helical molecules. Significant problems in the interpretation of PISEMA spectra may arise for systems that do not form perfectly defined secondary structures, like α-helices, or the signal pattern is disturbed by molecular motion. Here, we present a new method that combines molecular dynamics simulation with tensorial orientational constraints (MDOC) and chemical shift tensor calculations for the simulation and interpretation of PISEMA-like spectra. The calculations include the spectra arising from non α-helical molecules and molecules with non-uniform intrinsic mobility. In a first step, dipolar or quadrupolar interaction tensors drive molecular rotations and reorientations to obtain the proper mean values as observed in corresponding NMR experiments. In a second step, the coordinate snapshots of the MDOC simulations are geometry optimized with the isotropic 15 N chemical shifts as constraints using Bond Polarization Theory (BPT) to provide reliable 15 N CS tensor data. The averaged dipolar 1 H-15 N couplings and the δzz tensor components can then be combined to simulate PISEMA patterns. We apply this method to the ß-helical peptide gramicidin A (gA) and demonstrate that this method enables the assignment of most PISEMA resonances. In addition, MDOC simulations provide local order parameters for the calculated sites. These local order parameters reveal large differences in backbone mobility between L- and D-amino acids of gA.

Theoretical study of interaction between temozolomide anticancer drug and hydroxyethyl carboxymethyl cellulose nanocarriers for targeted drug delivery by DFT quantum mechanical calculation

In this article for the first time the quantum calculations of 3-methyl-4-oxoimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (Temozolomide) in HCM-Cellulose Substrate are evaluated using the B3LYP/6-31G level of theory. The non-bonded interaction effects of the molecule Temozolomide, HCM-Cellulose on the electronic properties, chemical shift tensors and natural charge have also been detected. Natural bond orbital analysis (NBO) suggests that Temozolomide as an electron donor and HCM-Cellulose acted as an electron acceptor in the Temozolomide/HCM-Cellulose complex. The electronic spectra of the Temozolomide drug and Temozolomide/HCM-Cellulose complex in were calculated by Time-Dependent Density Functional Theory (TD-DFT) for the investigation of the adsorption effect of the Temozolomide drug over HCM-Cellulose on maximum wavelength. As a result, the feasibility of using HCM-Cellulose to deliver Temozolomide to diseased cells has been established.

Experimentally Established 15N NMR Absolute Shielding Scale for Theoretical Calculations.

The nitrogen atom of 2,6-di-tert-butyl-N,N-diethylpyridin-4-amine (DEAP) is not available for non-covalent interactions. This molecule has been used to define the reference 15N NMR absolute chemical shielding (σref) required to convert between the chemical shift scale used in experiments and the absolute shielding scale used in theoretical calculations. The accuracy of the obtained σref was tested for solid samples of acetanilide-15N, the protonated homodimer of pyridine-15N, and poly(4-vinylpyridine-15N). Experimental 15N NMR chemical shift tensors were compared to 15N NMR shielding tensors calculated using the TPSSh, B3LYP, and ωB97XD functionals and the polarizable continuum model approximation. General recommendations are given for the smallest reliable basis set size. The reported structure of DEAP can be used to calculate σref for any other calculation method.

Acceleration of indirect detection 195Pt solid-state NMR experiments by sideband selective excitation or alternative indirect sampling schemes

The measurement of the of chemical shift (CS) tensors via solid-state NMR (ssNMR) spectroscopy has proven to be a powerful probe of structure for organic molecules, biomolecules, and inorganic materials. However, when measuring the NMR spectra of heavy spin-1/2 isotopes the chemical shift anisotropy (CSA) is commonly on the order of thousands of parts per million, which makes acquisition of NMR spectra difficult due to the low NMR sensitivity imposed by the breadth of the signals and challenges in uniformly exciting the NMR spectrum. We have recently shown that complete 195Pt NMR spectra could be rapidly measured by using 195Pt saturation or excitation selective long pulses (SLP) with multiple rotor-cycle durations and RF fields less than 50 kHz into 1H{195Pt} or 1H-31P{195Pt} PE S-RESPDOR, TONE D-HMQC-4, J-resolved, and J-HMQC pulse sequences. The SLP only provide signal or dephasing when they are applied on resonance with a spinning sideband. The magic angle spinning 195Pt NMR spectrum is reconstructed in the sideband selective NMR experiments by acquiring 1D NMR spectra at variable 195Pt pulse offsets. In this work, we present a detailed investigation of the specific pulse conditions required for the ideal performance of sideband selective experiments. Sideband selective experiments are shown to be able to accurately reproduce MAS NMR spectra with minimal distortions of relative sideband intensities. It is also demonstrated that a 195Pt NMR spectrum indirectly detected with HMQC can be rapidly obtained by acquiring a single rotor cycle of indirect dimension evolution points. We dub this method One Rotor Cycle of Acquisition (ORCA) HMQC. Sideband selective experiments and ORCA HMQC experiments are shown to provide a one order of magnitude improvement in experiment times as compared to conventional wideline HMQC experiments.

Solid-State 19F NMR Chemical Shift in Square-Planar Nickel-Fluoride Complexes Linked by Halogen Bonds.

The halogen bond (XB) is a highly directional class of noncovalent interactions widely explored by experimental and computational studies. However, the NMR signature of the XB has attracted limited attention. The prediction and analysis of the solid-state NMR (SSNMR) chemical shift tensor provide useful strategies to better understand XB interactions. In this work, we employ a computational protocol for modeling and analyzing the 19F SSNMR chemical shifts previously measured in a family of square-planar trans NiII-L2-iodoaryl-fluoride (L = PEt3) complexes capable of forming self-complementary networks held by a NiF···I(C) halogen bond [Thangavadivale, V.; Chem. Sci. 2018, 9, 3767-3781]. To understand how the 19F NMR resonances of the nickel-bonded fluoride are affected by the XB, we investigate the origin of the shielding in trans-[NiF(2,3,5,6-C6F4I)(PEt3)2], trans-[NiF(2,3,4,5-C6F4I)(PEt3)2], and trans-[NiF(C6F5)(PEt3)2] in the solid state, where a XB is present in the two former systems but not in the last. We perform the 19F NMR chemical shift calculations both in periodic and molecular models. The results show that the crystal packing has little influence on the NMR signatures of the XB, and the NMR can be modeled successfully with a pair of molecules interacting via the XB. Thus, the observed difference in chemical shift between solid-state and solution NMR can be essentially attributed to the XB interaction. The very high shielding of the fluoride and its driving contributor, the most shielded component of the chemical shift tensor, are well reproduced at the 2c-ZORA level. Analysis of the factors controlling the shielding shows how the highest occupied Ni/F orbitals shield the fluoride in the directions perpendicular to the Ni-F bond and specifically perpendicular to the coordination plane. This shielding arises from the magnetic coupling of the Ni(3d)/F(2p lone pair) orbitals with the vacant σNi-F* orbital, thereby rationalizing the very highly upfield (shielded) resonance of the component (δ33) along this direction. We show that these features are characteristic of square-planar nickel-fluoride complexes. The deshielding of the fluoride in the halogen-bonded systems is attributed to an increase in the energy gap between the occupied and vacant orbitals that are mostly responsible for the paramagnetic terms, notably along the most shielded direction.

Machine Learning Full NMR Chemical Shift Tensors of Silicon Oxides with Equivariant Graph Neural Networks.

The nuclear magnetic resonance (NMR) chemical shift tensor is a highly sensitive probe of the electronic structure of an atom and furthermore its local structure. Recently, machine learning has been applied to NMR in the prediction of isotropic chemical shifts from a structure. Current machine learning models, however, often ignore the full chemical shift tensor for the easier-to-predict isotropic chemical shift, effectively ignoring a multitude of structural information available in the NMR chemical shift tensor. Here we use an equivariant graph neural network (GNN) to predict full 29Si chemical shift tensors in silicate materials. The equivariant GNN model predicts full tensors to a mean absolute error of 1.05 ppm and is able to accurately determine the magnitude, anisotropy, and tensor orientation in a diverse set of silicon oxide local structures. When compared with other models, the equivariant GNN model outperforms the state-of-the-art machine learning models by 53%. The equivariant GNN model also outperforms historic analytical models by 57% for isotropic chemical shift and 91% for anisotropy. The software is available as a simple-to-use open-source repository, allowing similar models to be created and trained with ease.

Simultaneous recoupling of chemical shift tensors of two nuclei by R-symmetry sequences

Chemical shift tensors (CSTs) are sensitive probes of structure and dynamics. R-symmetry pulse sequences (RNCSA) can efficiently recouple CSTs of varying magnitudes in magic angle spinning (MAS) NMR experiments, for a broad range of conditions and MAS frequencies. Herein, we introduce dual-channel R-symmetry pulse sequences for simultaneously recording CSTs of two different nuclei in a single experiment (DORNE-CSA). We demonstrate the performance of DORNE-CSA sequences for simultaneous measurement of 13C and 15N CSTs, on a U-13C,15N-labeled microcrystalline l-histidine. We show that the DORNE-CSA method is robust, provides accurate CST parameters, and takes only half of the measurement time compared to a pair of RNCSA experiments otherwise required for recording the CSTs of individual nuclei. DORNE-CSA approach is broadly applicable to a wide range of biological and inorganic systems.

Chemical shift tensors as probes of chalcogen bonds: solid-state NMR study of telluradiazole-XCN− (X = O, S, Se) salt cocrystals

We report experimental 125Te magic-angle spinning solid-state nuclear magnetic resonance (MAS NMR) measurements of the tellurium chemical shift (CS) tensors in three [K(18-crown-6)]+ 3,4-dicyano-1,2,5-telluradiazole-XCN− (X = O, S, Se) salt cocrystals featuring chalcogen bonds. These data are compared to those for pure 3,4-dicyano-1,2,5-telluradiazole (1). A reduction in the span of the 125Te CS tensor is consistently noted in the salt cocrystals compared to pure 1. Isotopically 15N-labelled [K(18-crown-6)]+[1-OC15N]−, which features a chalcogen bond between Te and the cyanate nitrogen atom, is synthesized using KOC15N, and the nitrogen CS tensors are measured for both samples via 15N slow MAS NMR spectroscopy. Possible dynamic disorder of the cyanate ions in KOCN is ruled out. Two crystallographically distinct nitrogen sites are resolved for the salt cocrystal. Upon formation of [K(18-crown-6)]+[1-OC15N]−, the 15N isotropic CS and CS tensor span both decrease relative to the values for pure KOC15N, and the axial symmetry of this tensor is lost. These findings are supplemented with a series of density functional theory calculations of magnetic shielding tensors using cluster models or periodic boundary conditions. Inclusion of spin–orbit relativistic effects in the calculation of tellurium shielding tensors is particularly important in achieving agreement with experiment.