Probable Isomers Research Articles

Analysis of complex mixtures of polyglycerol fatty esters using liquid chromatography and high-resolution mass spectrometry: Retention, structural and relative composition study

Polyglycerol esters (PGEs), produced by esterification of fatty acids on polyglycerols, were analysed by High Resolution Mass Spectrometry (HRMS), HPLC-MS and U-HPLC-MS. A structural study of PGEs in 4 samples synthesised by the Gattefossé company was carried out using an elemental analysis of HRMS spectra and modelling of all probable isomers and cyclic structures. The results were used to construct a structural database of all species present in the 4 samples. After an assessment of the selectivity of 5 reversed phase columns: Aeris Widepore XB-C8, 3.6 µm, 2.1 × 150 mm (Phenomenex), Acquity CSH C18 1.7 µm 2.1 × 50 mm, Acquity CSH Phenyl-Hexyl 1.7 µm 2.1 × 50 mm, Acquity CSH Fluoro-Phenyl 1.7 µm 2.1 × 50 mm (Waters Co.) and Kinetex F5 1.7 µm 2.1 × 100 mm (Phenomenex), HPLC-MS and U-HPLC-MS analyses were performed on an Aeris Widepore XB-C8 (Phenomenex) column (HPLC) and Acquity CSH Fluoro-Phenyl (Waters) column (U-HPLC) with aqueous formic acid /acetonitrile in gradient mode. The separation was optimised with 10 min (HPLC) and 5 min (U-HPLC) of gradient. The detection, performed on a QDA detector (Waters), produced extracted ion chromatograms (XICs) based on all adducts identified in the HRMS analysis. HPLC and U-HPLC analyses showed the different mono- and di-ester species and provided relative quantification of all identified constituents. The combined analyses of the HRMS, HPLC-MS and U-HPLC-MS results were used to compare the different PGE batches and quantify the molecular constituents according to their relative abundance, for these complex mixtures. With HPLC and U-HPLC analyses, using 2 different gradient times and 2 different selectivity columns, and comparing the retention factors and log P of the different species, it was possible to link structural identification and relative quantification of all PGEs identified in the samples.

Structures of aniline(pyrrole)+, aniline(ethanol)+, and aniline-(benzene)+

Molecular structures of aniline(pyrrole)+, aniline(ethanol)+, and aniline(benzene)+ produced via resonance two-photon ionization at 266 nm were analyzed by infrared predissociation spectroscopy coupled with tandem mass spectrometry. Structural optimization and frequency calculation using density functional theory were carried out to suggest the most probable isomers which are in good agreement with the observed infrared absorption spectra. Intermolecular bonds in the cluster ions were formed such that the electronegative oxygen atom of the solvent molecule or the pi electron of the aromatic ring forms a hydrogen bonding to NH of aniline.

Nonconventional Hydrogen Bonds between Silver Anion and Nucleobases: Size-Selected Anion Photoelectron Spectroscopy and Density Functional Calculations.

We conducted combined gas-phase anion photoelectron spectroscopy and density functional theory studies on nucleobase-silver complexes. The most probable structures of the nucleobase-Ag- complexes were determined by comparing the theoretical calculations with the experimental measurements. The vertical detachment energies (VDEs) of uracil-Ag-, thymine-Ag-, cytosine-Ag-, and guanine-Ag- were estimated to be 2.18 ± 0.08, 2.11 ± 0.08, 2.04 ± 0.08, and 2.20 ± 0.08 eV, respectively, based on their photoelectron spectra. Adenine-Ag- has two isomers coexisting in the experiment; the experimental VDEs of the two isomers are 2.18 and 2.53 eV, respectively. In the most probable isomers of nucleobases-Ag-, uracil, thymine, and cytosine interact with Ag- anion via N-H···Ag and C-H···Ag hydrogen bonds, while adenine and guanine interact with Ag- anion through two N-H···Ag hydrogen bonds. The N-H···Ag hydrogen bonds can be characterized as medium or strong hydrogen bonds. It is found that binding sites of the Ag anion to the nucleobases are affected by the deprotonation energies and the steric effects of two adjacent X-H groups.

Isomeric complexity of glycosylation documented by MSn.

Re-analysis of two breast cancer cell lines, MCF-7 and MDA-MB-231, has shown multiple isomeric structures exposed by sequential mass spectrometry, MS n . Several released glycan compositions were re-evaluated, which indicated variations in polylactosamine and fucosylation structures. Probable isomer numbers, when considering both stereo and structural entities, are significant and the varying types are mentioned. The structural isomers of linkage position are most frequently considered, while stereo isomers are usually assumed from biosynthetic data. Evaluation of any new sample should be cautious and merits careful attention to empirical data. While isomers are usually considered a chromatographic problem (e.g., LCMS, IMMS) and most frequently considered a separations problem, such results will always be challenged by identification and documentation. MSn data provide a direct spatial solution that includes spectral data for characterization (mass and abundance) supported by a universal library match feature.

Quantifying Dimer and Trimer Formation by Tri-n-butyl Phosphates in n-Dodecane: Molecular Dynamics Simulations.

Tri-n-butyl phosphate (TBP), a representative of neutral organophosphorous ligands, is an important extractant used in the solvent extraction process for the recovery of uranium and plutonium from spent nuclear fuel. Microscopic pictures of TBP isomerism and its behavior in n-dodecane diluent were investigated utilizing MD simulations with previously optimized force field parameters for TBP and n-dodecane. Potential mean force (PMF) calculations on a single TBP molecule show seven probable TBP isomers. Radial distribution functions (RDFs) of TBP suggest the existence of TBP trimers at high TBP concentrations in addition to dimers. 2D PMF calculations were performed to determine the angle and distance criteria for TBP trimers. The dimerization and trimerization constants of TBP in n-dodecane were obtained and match our own experimental values using the FTIR technique. The new insights into the conformational behaviors of the TBP molecule as a monomer and as part of an aggregate could greatly aid in the understanding of the complexation between TBP and metal ions in a solvent extraction system.

Modified Biginelli reaction in the synthesis of chromenopyrimidobenzimidazolones

Biginelli reaction of 4-hydroxychromen-2-one with aromatic aldehydes and biazanucleophiles was investigated. The character of the substituent in the aromatic aldehyde and the reaction conditions affect its direction. The possibility to separate two probable regio isomers and the preparation of the chromenopyrimidobenzimidazolone with angular junction was demonstrated. The use of nuclear Overhauser effect (NOE 1D) made it possible to establish the spatial interaction between ortho-protons of chromene and benzimidazole fragments additionally confirming the structure of the obtained compound. The identification of the possible intermediates in the case of reacting 3-methyl-1H-pyrazol-5-amine as the azabinucleophile confirms the assumed scheme of 2H-chromen-2-ones formation under the applied conditions.

Electronic structure analysis of isomeric preferences of canonical and zwitterionic forms of lornoxicam

Lornoxicam, is a non-steroidal anti-inflammatory drug (NSAID) and has analgesic, anti-inflammatory and antipyretic activity. Various polymorphic forms of drugs belonging to oxicam class are known in the literature and study of their polymorphic behavior has become a research interest over the past few years. Due to the differences in the conformational arrangement of the molecules in the crystal lattice, polymorphic forms of a drug substance can exhibit different physicochemical properties–solubility, density, dissolution, pKa, etc. Density functional (DFT) study has been carried out on various canonical and zwitterionic forms of lornoxicam. The electronic level details revealed that, the existence of polymorphism in lornoxicam can be traced to the prototropic exchange which helps in the interconversion of one polymorph to the other. Electronic structures of all the probable isomers of lornoxicam at HF, B3LYP and M06L levels using 6-31+G(d) basis set have been analyzed. The comparative analysis of their relative Gibbs free energies in the gas, solution and explicit water phase revealed that the form of global minimum structure differs with respect to the varied conditions. Microsolvation calculations show that three water (3W) molecules are sufficient to stabilize the zwitterion ZO. Therefore, transition of canonical to zwitterionic form can happen under the influence of explicit water molecules. Further, transition state studies point out easy conversion between the two zwitterionic states (ZN↔ZO). This phenomenon can be attributed to the observed polymorphism in lornoxicam.

Oxidation by-products formation of microcystin-LR exposed to UV/H2O2: Toward the generative mechanism and biological toxicity

The presence of microcystins (MCs) in water sources is of concern due to their direct threats to human health and potential to form oxidation by-products (OBPs) in finished water. To control the environmental risk of MCs related OBPs, we evaluated their generative mechanisms and biological toxicity by mass spectrometry technology and molecular toxicity experiment. Exposed to UV/H2O2, model toxin microcystin-LR (MCLR) in clean water was quickly transformed but successively generated seven types of MCLR-OBPs with the chemical formulas of C49H74N10O13, C49H76N10O14, C49H78N10O16, C49H76N10O15, C37H58N10O12, C33H54N10O12, and C34H54N10O12. Probable isomers for each MCLR-OBP type were then separated and identified, indicating the aromatic ring and conjugated diene in Adda and the CC bond in Mdha were the major target sites of oxidation. Though subsequent toxicology data showed the toxicity of MCLR-OBPs on protein phosphatases 1 and 2A decreased with the extending of treatment by and large, they still possessed considerable biological toxicity (especially for product d). Influenced by MCLR-OBP distribution, concentration and residual toxicity, the secondary pollution of MCLR-OBPs in drinking water also deserved further attention even though MCLR was totally destroyed.

On the reliability of the corrected semiempirical quantum chemical method (PM6-DH2) for assigning the protonation states in HIV-1 protease/inhibitor complexes

A novel computational protocol for determining the most probable protonation states in protein/ligand complexes is presented. The method consists in treating large parts of the enzyme using the corrected semiempirical quantum chemical (QM) method – PM6-D2 for optimization and PM6-DH2 for single-point energies – while the rest is calculated using molecular mechanics (MM) within a hybrid QM/MM fashion. The surrounding solvent is approximated by an implicit model. This approach is applied to two model systems, two different carboxylate pairs in one general and one unique HIV-1 protease/inhibitor complex. The effect of the size of the movable QM part is investigated in a series of several sizes, 3-, 6-, 8- and 10-Å regions surrounding the inhibitor. For the smallest region (< 450 atoms) the computationally more costly DFT QM/MM optimizations are performed as a check of the correctness. Proton transfer (PT) phenomena occur at both the PM6-D2 and DFT levels, which underlines the requirement for a QM approach. The barriers of PT are checked in model carboxylic acid pairs using the highly accurate MP2 and CCSD(T) values. An important result of this study is the fine-tuning of the protocol which can be used in further applications; its limitations are also shown, pointing to future developments. The calculations reveal which protonation variants of the active site are the most stable. In conclusion, the presented protocol can also be utilized for defining probable isomers in biomolecular systems. It can also serve as a preparatory step for further interaction-energy and binding-score calculations.

Structure, Dynamics, and Energetics of Lysobisphosphatidic Acid (LBPA) Isomers

Lysobisphosphatidic acid (LBPA), or bis(monoacylglycerol)phosphate, is a very interesting lipid, that is mainly found in late endosomes. It has several intriguing characteristics, which differ from those of other animal glycerophospholipids, that may be related to its specific functions, particularly in the metabolism of cholesterol. Its phosphodiester group is bonded at the sn-1 (sn-1') positions of the glycerols rather than at sn-3 (sn-3'); the position of the two fatty acid chains is still under debate but, increasingly, arguments favor the sn-2, sn-2' position in the native molecule, whereas isolation procedures or acidic conditions lead to the thermodynamically more stable sn-3, sn-3' structure. Because of these peculiar features, it can be expected that LBPA shape and interactions with membrane lipids and proteins are related to its structure at the molecular level. We applied quantum mechanical methods to study the structures and stabilities of the 2,2' and 3,3' LBPA isomers, using a step-by-step procedure from glycerol to precursors (in vitro syntheses) and to the final isoforms. The structures of the two positional LBPA isomers are substantially different, showing that the binding positions of the fatty acid chains on the glycerol backbone determine the shape of the LBPA molecule and thus, possibly, its functions. The 3,3' LBPA structures obtained are more stable with respect to the 2,2' form, as expected from experiment. If one argues that the in vivo synthesis starts from the present glycerol conformers and considering the most stable bis(glycero)phosphate structures, the 2,2' isoform should be the most probable isomer.

ISOMER SPECTRUM OF C30 CLUSTER AND THE GROWTH DYNAMICS

We calculated the isomer spectrum of C 30 cluster by time-going-backward quasi-dynamics method and performed molecular dynamic simulations of the cluster growth in He buffer gas at 2500 K. Based on geometrical shapes, the isomers can be classified into closed cages, open cages, bowls, sheets and other irregular shapes. Although potential energies and free energies of the sheet isomers are much higher than those of the closed cage isomers, the dynamical simulations show that the sheet isomers rather than the cage isomers dominate in the resultant clusters at the simulation temperature and the most probable sheet isomer lies on the 47th level counted from the bottom one of the isomer spectrum.

Statistical model for small clusters transforming from one isomer to another

Based on the fact that the kinetic energy of one atom in small cluster still obeys the Boltzmann distribution, a statistical model is developed to predict the time consumed by a small cluster transforming from one isomer to another and is tested by vast molecular dynamics simulations of C(12) isomers transformation in helium gas at high temperatures (2000-3500 K). Extrapolating the model to lower temperatures, we found that the time for the most probable isomer of C(12) formed at 2500 K turning into the most stable one is more than 10(12) years at room temperature.

Theoretical prediction of the growth probabilities for cluster isomers

Theoretically predicting probabilities of the various isomers in the cluster growth is important because of the difficulty in characterizing structure of clusters. Considering that relative abundance of each isomer formed at high temperature could be obtained through molecular dynamics，what the problem comes down to is how these isomers transform from one to another at room temperature. We developed a statistical mechanics model，and obtained the analytic relationship between the temperature and the transformation time from one isomer to another. Taking cluster C 12 as an example，it is shown that the time for the most probable isomer formed at 2500 K turning into the isomer with the lowest potential energy at room temperature is longer than.

Density functional calculation of the geometric and magnetic properties of MPb10（M=Ti，V，Cr，Cu，Pd） clusters

The geometric and magnetic properties of MPb10 （M=Ti，V，Cr，Cu，Pd）clusters with four probable isomers have been studied using the generalized grandient approximation based on density functional theory. It was found that the D4d structures of MPb10 （M=Ti，V，Cr，Cu，Pd） have the highest binding energy and largest energy gaps among the four possible isomers, indicating that the D4d structure is the ground statess of MPb10 cluster with high kinetical stability. The magnetism study shows that the ground states of TiPb10，VPb10 and CuPb10 clusters have 2 μB, 1 μB and 1 μB magnetic moments, respectively. For M=Ti and Cu, the magnetic ordering of MPb10 clusters is in a weak ferromagnetic arrangement between M and Pb atoms, while there is both weak ferromagnetic and weak antiferromagnetic arrangements between Cu and Pb atoms for the CuPb10 cluster. On the other hand, there is no magnetic moment in the CrPb10 and PdPb10 clusters. Thus, the magnetic properties of MPb10 clusters could be tuned by doping different transition metal atoms into Pb10 cage.

Computational studies of the binding mode and 3D-QSAR analyses of symmetric formimidoester disulfides: a new class of non-nucleoside HIV-1 reverse transcriptase inhibitor

Symmetric formimidoester disulfides (DSs) have recently been identified as a new class of potent non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors. Given that three geometric isomers for DSs are possible, a computational strategy based on molecular docking studies, followed by comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) was used in order to identify the most probable DS isomer interacting with RT, to elucidate the atomic details of the RT/DS interaction, and to identify key features impacting DS antiretroviral activity. The CoMFA model was found to be the more predictive, with values of r(2)ncv, r(2)cv, SEE = 0.264, F = 80, and r(2)pred=0.73.

51V NMR Chemical Shifts Calculated from QM/MM Models of Vanadium Chloroperoxidase

(51)V NMR chemical shifts calculated from QM/MM-optimized (QM=quantum mechanical; MM=molecular mechanical) models of vanadium-dependent chloroperoxidase (VCPO) are presented. An extensive number of protonation states for the vanadium cofactor (active site of the protein) and a number of probable positional isomers for each of the protonation states are considered. The size of the QM region is increased incrementally to observe the convergence behavior of the (51)V NMR chemical shifts. A total of 40 models are assessed by comparison to experimental solid-state (51)V NMR results recently reported in the literature. Isotropic chemical shifts are found to be a poor indicator of the protonation state; however, anisotropic chemical shifts and the nuclear quadrupole tensors appear to be sensitive to changes in the proton environment of the vanadium nuclei. This detailed investigation of the (51)V NMR chemical shifts computed from QM/MM models provides further evidence that the ground state is either a triply protonated (one axial water and one equatorial hydroxyl group) or a doubly protonated vanadate moiety in VCPO. Particular attention is given to the electrostatic and geometric effects of the protein environment. This is the first study to compute anisotropic NMR chemical shifts from QM/MM models of an active metalloprotein for direct comparison with solid-state MAS NMR data. This theoretical approach enhances the potential use of experimental solid-state NMR spectroscopy for the structural determination of metalloproteins.

Parity alternation of linear ground-state C nS 2− ( n = 6–18) clusters

Making use of the software of molecular graphics, we designed many patterns of C n S 2− ( n = 6–18) models. We carried out geometry optimization and calculation on vibrational frequency by means of the B3LYP density functional method. The most probable ground-state isomers of C n S 2− ( n = 6–18) are linear with the sulfur atom located at one end of the C n chain. When n is even, the isomer is polyacetylene-like. The C n S 2− ( n = 6–18) with even number of carbon atoms are more stable than those with odd number, matching the peak pattern observed in studies of mass spectrometry. The trend of odd/even alternation is also detected in certain bond length, atomic charge, electronic configuration, the highest vibrational frequency, energy difference, electron detachment energy, and incremental binding energy of the most probable ground-state isomers.

Geometric structures, electronic properties, and magnetism of M2Sn17(M=Ni，Mn)and their anions

The geometric structures and magnetism of the three probable isomers for Ni2Sn17，Mn2Sn17，［Ni2Sn17］4- and ［Mn2Sn17］2- have been studied using the generalized gradient approximation based on density functional theory. It was found that the D2d structures of Ni2Sn17，Mn2Sn17，［Ni2Sn17］4- and ［Mn2Sn17］2- are the most stable structures among the three possible isomers. The study shows that the D2d structure and the D4d structure of Ni2Sn17 have spin-splitting, leading to the magnetic moment 4μB and 2μB， respectively, and there is weak ferromagnetic interaction between the Ni and Sn atoms for the D2d structure and the D4d structure. However, there is no magnetic moment in the D4h structure. On the other hand, the D2d, D4d, and D4h Mn2Sn17 have 2μB，6μB and 2μB magnetic moments, respectively. It is interesting that there is weak antiferromagnetic interaction and weak ferromagnetic interaction between Mn and Sn atoms for the D2d and D4h structures, respectively, while there is not only weak ferromagnetic interaction but also weak antiferromagnetic interaction between Mn and Sn atoms in the D4d structure. Finally, It is worth noting that all their anion counterparts of ［Ni2Sn17］4- and ［Mn2Sn17］2- have closed electronic configurations, showing no magnetic moment.

Quantitation of Carcinogenic Heterocyclic Aromatic Amines and Detection of Novel Heterocyclic Aromatic Amines in Cooked Meats and Grill Scrapings by HPLC/ESI-MS

A tandem solid-phase extraction method was used to isolate carcinogenic heterocyclic aromatic amines (HAAs) from cooked meats. The following 10 HAAs were identified by HPLC/ESI-MS/MS: 2-amino-9H-pyrido[2,3-b]indole (2-AalphaC), 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAalphaC), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3-methylimidazo[4,5-f]quinoxaline (IQx), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (8-MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx), 2-amino-3,7,8-trimethylimidazo[4,5-f]quinoxaline (7,8-DiMeIQx), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-1,7,9-trimethylimidazo[4,5-g]quinoxaline (7,9-DiMeIgQx), and 2-amino-1-methylimidazo[4,5-b]quinoline (IQ[4,5-b]); the latter HAA has not previously been reported in cooked meats. The concentrations of these HAAs ranged from <0.03 to 15 ppb in cooked meats and poultry, to 75 ppb in cooked beef extract, and to 85 ppb in grill scrapings. The product ion scan mode was used to confirm the identities of these HAAs. Six other compounds were detected that appear to contain the N-methylimidazoquinoxaline skeleton on the basis of their product ion spectra, and these compounds are probable isomers of IQx, 8-MeIQx, and DiMeIQx. A number of known HAAs and novel HAAs of unknown genotoxic potential are formed at appreciable levels in cooked meats.

A molecular modeling and QSAR study of suppressors of the growth of Trypanosoma cruzi epimastigotes

In this work, we have used molecular modeling and QSAR tools to study 18 dithiocarbamate suppressors of the growth of Trypanosoma cruzi epimastigotes, which have been reported in the literature as superoxide dismutase (SOD) inhibitors. The principal component analysis (PCA) showed that the descriptors superficial area, heat of formation, logarithm of the partition coefficient, charge of the nitrogen atom from the dithiocarbamate group and Charges of the two carbon atoms adjacent to that nitrogen are responsible for the classification between the higher and lower trypanomicid activity. Using multiple linear regression (MLR) and docking methods it was possible to identify the probable bioactive isomers that suppress of the growth of T. cruzi epimastigotes. Our best partial least square (PLS) model obtained with these six descriptors yields a good correlation between experimental and predicted biological activities and compares two different SODs as possible target for interaction with the dithiocarbamates.