15N NMR Chemical Shifts Research Articles

Fibrils of Truncated Pyroglutamyl-Modified Aβ Peptide Exhibit a Similar Structure as Wildtype Mature Aβ Fibrils

Fibrillation of differently modified amyloid β peptides and deposition as senile plaques are hallmarks of Alzheimer’s disease. N-terminally truncated variants, where the glutamate residue 3 is converted into cyclic pyroglutamate (pGlu), form particularly toxic aggregates. We compare the molecular structure and dynamics of fibrils grown from wildtype Aβ(1–40) and pGlu3-Aβ(3–40) on the single amino acid level. Thioflavin T fluorescence, electron microscopy, and X-ray diffraction reveal the general morphology of the amyloid fibrils. We found good agreement between the 13C and 15N NMR chemical shifts indicative for a similar secondary structure of both fibrils. A well-known interresidual contact between the two β-strands of the Aβ fibrils could be confirmed by the detection of interresidual cross peaks in a 13C-13C NMR correlation spectrum between the side chains of Phe 19 and Leu 34. Small differences in the molecular dynamics of residues in the proximity to the pyroglutamyl-modified N-terminus were observed as measured by DIPSHIFT order parameter experiments.

Substituent Effects on the [N-I-N](+) Halogen Bond.

We have investigated the influence of electron density on the three-center [N–I–N]+ halogen bond. A series of [bis(pyridine)iodine]+ and [1,2-bis((pyridine-2-ylethynyl)benzene)iodine]+ BF4– complexes substituted with electron withdrawing and donating functionalities in the para-position of their pyridine nitrogen were synthesized and studied by spectroscopic and computational methods. The systematic change of electron density of the pyridine nitrogens upon alteration of the para-substituent (NO2, CF3, H, F, Me, OMe, NMe2) was confirmed by 15N NMR and by computation of the natural atomic population and the π electron population of the nitrogen atoms. Formation of the [N–I–N]+ halogen bond resulted in >100 ppm 15N NMR coordination shifts. Substituent effects on the 15N NMR chemical shift are governed by the π population rather than the total electron population at the nitrogens. Isotopic perturbation of equilibrium NMR studies along with computation on the DFT level indicate that all studied systems possess static, symmetric [N–I–N]+ halogen bonds, independent of their electron density. This was further confirmed by single crystal X-ray diffraction data of 4-substituted [bis(pyridine)iodine]+ complexes. An increased electron density of the halogen bond acceptor stabilizes the [N···I···N]+ bond, whereas electron deficiency reduces the stability of the complexes, as demonstrated by UV-kinetics and computation. In contrast, the N–I bond length is virtually unaffected by changes of the electron density. The understanding of electronic effects on the [N–X–N]+ halogen bond is expected to provide a useful handle for the modulation of the reactivity of [bis(pyridine)halogen]+-type synthetic reagents.

A systematic study on RNA NMR chemical shift calculation based on the automated fragmentation QM/MM approach

1H, 13C and 15N NMR chemical shift calculations on RNAs were performed using the automated fragmentation quantum mechanics/molecular mechanics (AF-QM/MM) approach.

DFT study on the tautomerism of organic linker 1H-imidazole-4,5-tetrazole (HIT)

In this study the tautomerism of 1H-imidazole-4,5-tetrazole (HIT) are investigated in liquid and gas phases using density functional theory. The intramolecular hydrogen bond proves to be the key factor for the stability and the chemical properties of the tautomers. Boltzmann population analysis shows that the probability for the existence of the most stable tautomers is prominent in both gas and liquid phases. The dipole moment of all the tautomers increases with increase in polarity of the medium considered. 15N NMR and 13C NMR chemical shift along with MESP predict that the nitrogen atoms in both tetrazole and imidazole rings are excellent metal coordination sites. The pKa value predicts that the tautomers to be acidic in nature. A linear relationship between the redox potential and the ionization potential shows that all the tautomers tend to lose electrons, hence can coordinate with metals strongly.

Intermolecular interactions in mixtures of 1-n-butyl-3-methylimidazolium acetate and water: Insights from IR, Raman, NMR spectroscopy and quantum chemistry calculations

The intermolecular interactions in 1-n-butyl-3-methylimidazolium acetate (BmimAc)/water mixture were studied by examining the mole fraction dependence of the vibrational modes measured with infrared and Raman spectroscopy, as well as of the 1H, 13C, 15N and 17O NMR chemical shifts. Quantum chemistry calculations were carried out to assign as clearly as possible the vibrational modes of the cation and anion as well as to get information on the expected effect of the mixture composition on the vibrational modes and charge distribution in BmimAc.The behavior of the obtained spectroscopic data is consistent with the physical picture that when water is added to BmimAc, the interactions between cation–anion are weakened in favor of those between water and anion. The clear spectral signature is associated with the strong blue/red shift of the stretching and bending modes of the C(2)–H, respectively. Consistently with this spectral behavior, the corresponding 1H and 13C chemical shifts decrease when adding water to BmimAc. The strengthening of the water–anion interactions is also traced back to both the blue shift of the νs(COO−) at around 1380cm−1 and ν(C–C) of acetate at around 920cm−1 as well as the blue shift of the δ(COO−) at around 637cm−1 and ω(COO−) at 615cm−1. The 1H, 13C and 17O chemical shifts of COO− are consistent with the corresponding spectral behavior.

Theoretical and experimental study of 15N NMR protonation shifts.

A combined theoretical and experimental study revealed that the nature of the upfield (shielding) protonation effect in 15N NMR originates in the change of the contribution of the sp(2)-hybridized nitrogen lone pair on protonation resulting in a marked shielding of nitrogen of about 100 ppm. On the contrary, for amine-type nitrogen, protonation of the nitrogen lone pair results in the deshielding protonation effect of about 25 ppm, so that the total deshielding protonation effect of about 10 ppm is due to the interplay of the contributions of adjacent natural bond orbitals. A versatile computational scheme for the calculation of 15N NMR chemical shifts of protonated nitrogen species and their neutral precursors is proposed at the density functional theory level taking into account solvent effects within the supermolecule solvation model.

Intramolecular Halogen Bonding in Solution: 15N, 13C, and 19F NMR Studies of Temperature and Solvent Effects

AbstractA model system for the investigation of intramolecular halogen bonds is introduced. Two molecules capable of intramolecular halogen bonding have been studied in comparison with eight control compounds by 15N, 13C, and 19F NMR spectroscopy. Iodine‐ and bromine‐centered halogen bonds are indicated by decreases in the 15N NMR chemical shifts of the halogen bond acceptor atom of approximately 6 and 1 ppm, respectively. 13C NMR chemical shifts of the alkynyl carbons in 2‐ethynylpyridine systems are good indicators of halogen bonding, with differences of up to 2.4 ppm between halogen‐bonded and related control compounds. Halogen bond strengths in different solvents, as indicated by 19F NMR chemical shifts, decrease in the following order: Cyclohexane > toluene > benzene > dichloromethane > acetone > pyridine. Chemical shift effects associated with the structural and electronic properties of intramolecular halogen‐bonded systems are modeled well by calculations at the B3LYP/6‐311+G(2d,p) level of theory.

Oligomeric complexes of some heteroaromatic ligands and aromatic diamines with rhodium and molybdenum tetracarboxylates: 13 C and 15 N CPMAS NMR and density functional theory studies

Seven new oligomeric complexes of 4,4'-bipyridine; 3,3'-bipyridine; benzene-1,4-diamine; benzene-1,3-diamine; benzene-1,2-diamine; and benzidine with rhodium tetraacetate, as well as 4,4'-bipyridine with molybdenum tetraacetate, have been obtained and investigated by elemental analysis and solid-state nuclear magnetic resonance spectroscopy, (13)C and (15)N CPMAS NMR. The known complexes of pyrazine with rhodium tetrabenzoate, benzoquinone with rhodium tetrapivalate, 4,4'-bipyridine with molybdenum tetrakistrifluoroacetate and the 1 : 1 complex of 2,2'-bipyridine with rhodium tetraacetate exhibiting axial-equatorial ligation mode have been obtained as well for comparison purposes. Elemental analysis revealed 1 : 1 complex stoichiometry of all complexes. The (15)N CPMAS NMR spectra of all new complexes consist of one narrow signal, indicating regular uniform structures. Benzidine forms a heterogeneous material, probably containing linear oligomers and products of further reactions. The complexes were characterized by the parameter complexation shift Δδ (Δδ = δcomplex - δligand). This parameter ranged from around -40 to -90 ppm in the case of heteroaromatic ligands, from around -12 to -22 ppm for diamines and from -16 to -31 ppm for the complexes of molybdenum tetracarboxylates with 4,4'-bipyridine. The experimental results have been supported by a density functional theory computation of (15)N NMR chemical shifts and complexation shifts at the non-relativistic Becke, three-parameter, Perdew-Wang 91/[6-311++G(2d,p), Stuttgart] and GGA-PBE/QZ4P levels of theory and at the relativistic scalar and spin-orbit zeroth order regular approximation/GGA-PBE/QZ4P level of theory. Nucleus-independent chemical shifts have been calculated for the selected compounds.

Analytical Characterization of FGF Signaling Complex

Fibroblast growth factors (FGF) are a family of growth hormones that act as regulators in key biological processes such as angiogenesis, wound healing, embryonic development and select endocrine signaling pathways. It is currently theorized that the mechanism of the interaction of FGF to their receptors, fibroblast growth factor receptors (FGFR) is greatly reliant upon the binding of heparin to FGFs. It is theorized that the D2 domain is the primary site for the FGF bind and interaction. The objective of this study is to characterize the structure of the FGF-D2 domain. A structural analog of heparin, sucrose octasulfate (SOS), is employed in this study to determine the role of heparin in the formation of the FGF-FGFR complex. Isothermal titration calorimetry experiments were preformed to assess the binding affinity of FGF and the D2 domain, these experiments indicate that human acidic FGF (FGF-1) binds to the D2 domain with high affinity in both the presence and absence of SOS (Kd(appa) ∼ 10−7 M and Kd(appa) ∼ 10−8 M respectively). Thermal denaturation experiments, monitored by far-UV CD, indicate that both FGF-1 and D2 domain undergo slight conformational changes as a result of binding and elucidates the presence of SOS stabilizes a 1:1 FGF-D2 domain complex. The FGF signaling complex, comprised of the FGF-1, the D2 domain, and SOS, structure elucidated by X-ray crystallography indicated that the complex exists as a 2:2:2 symmetrical conjugation. Analysis via 2D 1H and 15N NMR chemical shift perturbation (CSP) has allowed for the accurate mapping of the SOS and FGF binding sites of the D2 domain. The data resulting from this study suggest that the primary role of heparin in the FGF signaling process is limited to stabilizing the FGF-FGFR complex.

Intermolecular Packing in B. mori Silk Fibroin: Multinuclear NMR Study of the Model Peptide (Ala-Gly)15 Defines a Heterogeneous Antiparallel Antipolar Mode of Assembly in the Silk II Form

We have previously suggested that crystalline Bombyx mori silk in silk II form (the silk structure after spinning) is not a simple antiparallel β-sheet but is intrinsically heterogeneous. Using the peptide (AG)15, we have obtained the first fully assigned high resolution solid state 1H NMR spectrum. Distinct heterogeneity was observed, in both 1H and 13C CP/MAS signals. Based on these results, a new model is proposed that contains two different packing arrangements of antiparallel β-sheets. The structures were energetically minimized by CASTEP calculation and used to calculate the solid state 1H, 13C, and 15N NMR chemical shifts using the GIPAW method. This new model was supported by good agreement between the calculated and observed 1H, 13C, and 15N chemical shifts and relative 1H–1H proximities obtained from 2D 1H DQMAS experiments. We conclude that the intermolecular packing of B. mori silk fibroin has been finally resolved.

Synthesis and NMR Analysis of 1,4‐Disubstituted 1,2,3‐Triazoles Tethered to Pyridine, Pyrimidine, and Pyrazine Rings

AbstractA combinatorial modular approach based on the “click” copper(I)‐catalysed azide–alkyne cycloaddition reaction was used to prepare a library of selected 1,4‐disubstituted 1,2,3‐triazoles differently functionalized with heteroaryl groups including pyridine, pyrimidine, and pyrazine. Three different copper(I) sources, i.e., CuSO4/sodium ascorbate, CuBr(PPh3)3, and (CuOTf)2·C6H6 were used to promote the coupling reactions of a range of aryl, heteroaryl, and heteroarylmethyl azides with alkyne “click” partners. As the target heteroaryl triazoles were designed to serve as advanced ligands or ligand precursors for metal coordination, they were fully characterized by 1H, 13C, and 15N NMR spectroscopy. The resonances were assigned on the basis of 1D and 2D NMR experiments. 1H–15N gs‐HMBC was used as a practical tool to determine 15N NMR chemical shifts at the natural abundance level of the 15N isotope.

Back Cover: Structural Biology of Cisplatin Complexes with Cellular Targets: The Adduct with Human Copper Chaperone Atox1 in Aqueous Solution (Chem. Eur. J. 37/2014)

Hybrid QM/MM simulations and molecular spectroscopy provide structural insights on cisplatin binding to the copper transporter Atox1 in water solution. A molecular model of the platinated protein is provided. In this model, the Pt atom binds to Cys12 and Cys15 while retaining its two cis ammine ligands. The calculated 1H, 13C, and 15N NMR chemical shifts and CD spectra of this model are in accord with experiment. For the complete story see the Full Paper by P. Carloni et al. on page 11719 ff.

Computational identification of a phospholipidosis toxicophore using 13C and 15N NMR-distance based fingerprints

Modified 3D-SDAR fingerprints combining 13C and 15N NMR chemical shifts augmented with inter-atomic distances were used to model the potential of chemicals to induce phospholipidosis (PLD). A curated dataset of 328 compounds (some of which were cationic amphiphilic drugs) was used to generate 3D-QSDAR models based on tessellations of the 3D-SDAR space with grids of different density. Composite PLS models averaging the aggregated predictions from 100 fully randomized individual models were generated. On each of the 100 runs, the activities of an external blind test set comprised of 294 proprietary chemicals were predicted and averaged to provide composite estimates of their PLD-inducing potentials (PLD+ if PLD is observed, otherwise PLD−). The best performing 3D-QSDAR model utilized a grid with a density of 8ppm×8ppm in the C–C region, 8ppm×20ppm in the C–N region and 20ppm×20ppm in the N–N region. The classification predictive performance parameters of this model evaluated on the basis of the external test set were as follows: accuracy=0.70, sensitivity=0.73 and specificity=0.66. A projection of the most frequently occurring bins on the standard coordinate space suggested a toxicophore composed of an aromatic ring with a centroid 3.5–7.5Å distant from an amino-group. The presence of a second aromatic ring separated by a 4–5Å spacer from the first ring and at a distance of between 5.5Å and 7Å from the amino-group was also associated with a PLD+ effect. These models provide comparable predictive performance to previously reported models for PLD with the added benefit of being based entirely on non-confidential, publicly available training data and with good predictive performance when tested in a rigorous, external validation exercise.

Performance of the M06 family of functionals in prediction of the charge transfer transition energies of the naphthalene–TCNE and pyrene–TCNE molecular complexes

The B3LYP and the M06 family of functionals were found to be of nearly equal efficiency for predicting the 13C and 15N NMR chemical shifts (which are ground state properties) of molecular complexes of TCNE with naphthalene and pyrene. But the B3LYP functional could not find any charge transfer (CT) absorption band of the complexes. The M06, M06-2X, M06-HF and M06-L functionals could find two CT absorption bands in CCl4 medium by a TDDFT calculation under the PCM formalism for solvation; the calculated CT transition energies are comparable with the reported experimental values, M06-2X and M06-L agreeing best with experiment.

Synthesis, spectroscopic and conformational analysis of 1,4-dihydroisonicotinic acid derivatives

Structural and conformational properties of 1,4-dihydroisonicotinic acid derivatives, characterized by ester, ketone or cyano functions at positions 3 and 5 in solid and liquid states have been investigated by X-ray analysis and nuclear magnetic resonance and supported by quantum chemical calculations. The dihydropyridine ring in each of the compounds exists in flattened boat-type conformation. The observed ring distortions around the C(4) and N(1) atoms are interrelated. The substituent at N(1) has great influence on nitrogen atom pyramidality. The 1H, 13C and 15N NMR chemical shifts and coupling constants are discussed in terms of their relationship to structural features such as character and position of the substituent in heterocycle, N-alkyl substitution and nitrogen lone pair delocalization within the conjugated system.

NMR Chemical Shifts of15N-Bearing Graphene

The 15N NMR chemical shifts of possible nitrogen-containing moieties at edges and defects of graphene are investigated by using the first-principles method. Our computational results show that pyridine-like and graphite-like N can be rather easily identified using the 15N NMR technique, in agreement with experiment. On the other hand, pyridinium-like 15N is hardly distinguished from the pyrrole-like one using the NMR, because these 15N nuclei give nearly overlapping signals. However, our simulations suggest that 1H NMR is useful to discriminate between them; the NMR chemical shifts of 1H directly bonded with pyridinium-like and pyrrole-like N along the armchair edge are estimated to be 0.8 and 10.1 ppm, respectively, while the corresponding chemical shift for pyridinium-like N along the zigzag edge is located between them. The 15N NMR signals for various moieties at edges we considered are found to be similar to the corresponding ones at defects except for pyridine-like nitrogens. Conversely, the 15N NMR chemical shifts are altered sensitively by the degree of aggregation of pyridine-like 15N atoms both along armchair edges and at defect sites. Interestingly, the graphite-like 15N doped along zigzag edges, which was attributed in our previous work to an active configuration for oxygen reduction reaction at the cathode of fuel cells, is identifiable via NMR irrespective of the details of samples such as edge terminations, dopant distributions, and graphene sizes.

A theoretical probe on the non-covalent interactions of sulfadoxine drug with pi-acceptors

A detailed analysis of the interaction between an antimalarial drug sulfadoxine and four pi-acceptors, tetrachloro-catechol, picric acid, chloranil, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone is presented in this study. The interaction of the amine, amide, methoxy, CH groups and π electron density of the drug molecule with the acceptors are studied using DFT method at M06-2X level of theory with 6-31G(d,p) basis set. The interaction energy of the complexes is calculated using M06-2X, M06-HF, B3LYP-D and MP2 methods with 6-31G(d,p) basis set. The role of weak interactions on the formation and stability of the complexes is discussed in detail. The two aromatic platforms of sulfadoxine play a major role in determining the stability of the complexes. The electron density difference maps have been plotted for the most stable drug interacting complexes to understand the changes in electron density delocalization upon the complex formation. The nature of the non-covalent interaction has been addressed from NCI plot. The infrared spectra calculated at M06-2X/6-31G(d,p) level of theory is used to characterize the most stable complexes. The SDOX-pi acceptor complexation leads to characteristic changes in the NMR spectra. The 13C, 1H, 17O and 15NNMR chemical shifts have been calculated using GIAO method at M06-2X/6-311+G(d,p)//M06-2X/6-31G(d,p) level of theory. The results obtained from this study confirm the role of non-covalent interactions on the function of the sulfadoxine drug.

The spectroscopic and the QTAIM properties of pyridine and phenanthroline derivatives using experimental and computational methods

The experimental and theoretical properties of ligands consisting of pyridine and phenanthroline derivatives have been studied. The results show a very high correlation between the experimental and theoretical spectroscopic properties of the ligands such as the IR, NMR chemical shift and UV. The carboxylic units in the ligands lead to increase in the dipole and anisotropic properties of the molecules while the methyl group lead to increase in the isotropic shielding tensor of the molecules. Most of the observed UV λmax in the ligands are predominantly excitation of electrons from the HOMO-2 or HOMO-1 or HOMO to the LUMO of the ligands. The ligand 2,2-dicarboxylphenanthroline (dcphn) is predicted to be the best starting material for non-linear optical (NLO) application due to its far higher first static hyperpolarizability tensor compare to other ligands and its lowest band gap. The same ligand can also be best for DNA binding because it has the lowest value of LUMO. The atomic charge of the nitrogen is found to be highly correlated with molecular HOMO, LUMO and non-Lewis orbital. The 15N NMR chemical shift is found to be highly correlated atomic anisotropy, energy and intra-atomic isotropic shielding tensor.

Quantum-chemical calculations of NMR chemical shifts of organic molecules: XIII. Accuracy of the calculation of 15N NMR chemical shifts of azines with account taken of solvation effects

Effects of solvation on the accuracy of the calculation of 15N chemical shifts in the azine series have been analyzed at the DFT/GIAO level of theory. The best results are obtained with the use of the Keal-Tozer KT2 functional in combination with the Dunning aug-cc-pVTZ basis set with inclusion of solvent effects according to the Tomasi polarizable continuum model (PCM). If specific solvation is strong, additional consideration of solvent effects in the supermolecule approximation is necessary with explicit inclusion of solvent molecules.

13C and 15N NMR chemical shifts of E. coli full-length H-NS protein

13C and 15N NMR chemical shifts of E. coli full-length H-NS protein