The nature of M–M bonding and aromaticity of [M2(NHCHNH)3]2(μ-E)2 (E?=?O, S; M?=?Nb, Mo, Tc, Ru, Rh) was investigated using atoms in molecules (AIM) theory, electron localization function (ELF), natural bond orbital (NBO) and molecular orbital analysis. These analyses led to the following main conclusions: in [M2(NHCHNH)3]2(μ-E)2 (E?=?O, S; M?=?Nb, Mo, Tc, Ru, Rh), the Nb–Nb, Ru–Ru, and Rh–Rh bonds belong to “metallic” bonds, whereas Mo–Mo and Tc–Tc drifted toward the “dative” side; all these bonds are partially covalent in character. The Nb–Nb, Mo–Mo, and Tc–Tc bonds are stronger than Ru–Ru and Rh–Rh bonds. The M–M bonds in [M2(NHCHNH)3]2(μ-S)2 are stronger than those in [M2(NHCHNH)3]2(μ-O)2 for M?=?Nb, Mo, Tc, and Ru. The NICS(1)ZZ values show that all of the studied molecules, except [Ru2(NHCHNH)3]2(μ-O)2, are aromaticity molecules. O-bridged compounds have more aromaticity than S-bridged compounds.
Graphical AbstractLeft Molecular graph, and right electron localization function (ELF) isosurface of [M2(NHCHNH)3]2(μ-E)2(E?=?O, S; M?=?Nb, Mo, Tc, Ru, Rh)
Similar to σ-hole interactions, the π-hole interaction has attracted much attention in recent years. According to the positive electrostatic potentials above and below the surface of inorganic heterocyclic compounds S2N2 and three SN2P2 isomers (heterocyclic compounds 1–4), and the negative electrostatic potential outside the X atom of XH3 (X = N, P, As), S2N2/SN2P2?XH3 (X = N, P, As) complexes were constructed and optimized at the MP2/aug-cc-pVTZ level. The X atom of XH3 (X = N, P, As) is almost perpendicular to the ring of the heterocyclic compounds. The π-hole interaction energy becomes greater as the trend goes from 1?XH3 to 4?XH3. These π-hole interactions are weak and belong to “closed-shell” noncovalent interactions. According to the energy decomposition analysis, of the three attractive terms, the dispersion energy contributes more than the electrostatic energy. The polarization effect also plays an important role in the formation of π-hole complexes, with the contrasting phenomena of decreasing electronic density in the π-hole region and increasing electric density outside the X atom of XH3 (X = N, P, As).
Graphical abstract Computed density difference plots for the complexes 3?NH 3 (a 1), 3?PH 3 (b 1), 3?AsH 3 (c 1) and electron density shifts for the complexes 3?NH 3 (a 2), 3?PH 3 (b 2),3?AsH 3 (c 2) on the 0.001 a.u. contour
Different subtypes of opioid receptors (OR) were activated in rats in vivo to study the activation effect on the heart’s resistance to ischemia and reperfusion. It has been established that administration of deltorphin II, a selective δ2-OR agonist, lowered the infarct size/area at risk index (IS/AAR) by 23%. Naltrexone, naloxone methiodide (an OR inhibitor not penetrating the blood-brain barrier (BBB)), and naltriben (δ2-antagonist) eliminated the cardioprotective effect of deltorphin II, while BNTX (a δ1-antagonist) produced no effect on the cardioprotective action of the δ2-agonist. The infarct-reducing effect of deltorphin II was eliminated by administration of chelerythrine (a protein kinase C (PKC) inhibitor), glibenclamide (a KATP-channels inhibitor), and 5-hydroxydecanoate (a mitochondrial KATP-channel blocker). Administration of other opioids did not reduce the IS/AAR index. It has been established that all the deltorphins manifest antiarrhythmic potency. Other opioids do not produce any effect on the incidence of arrhythmia occurrences. The antiarrhythmic effect of deltorphin II was eliminated by preliminary administration of naltrexone, naloxone methiodide, and naltriben, but BNTX did not affect the δ2-agonist’s anti-arrhythmic effect. The preliminary administration of chelerythrine, a PKC inhibitor, eliminated the δ2 agonist’s antiarrhythmic action. However, glibenclamide and 5-hydroxydecanoate did not alter the antiarrhythmic effect by deltorphin II. Therefore, activation of the peripheral δ2-ORs reduces the infarct size and prevents the onset of arrhythmias. The antiarrhythmic effect of the δ2-OR stimulation is mediated by activating PKC and opening the mitochondrial KATP-channels. PKC participates in the antiarrhythmic effect of the δ2-OR activation, but this effect does not depend on the condition of KATP-channels. 相似文献
Sodium Nitroprusside (SNP) and S-Nitrosoglutathione (GSNO) differently affect mitochondrial H2O2 release at Complex-I. mM SNP increases while GSNO decreases the release induced by succinate alone or added on top of NAD-linked
substrates. Stimulation likely depends on Nitric Oxide (.NO) (released by SNP but not by GSNO) inhibiting cytochrome oxidase and mitochondrial respiration. Preincubations with SNP
or high GSNO (10 mM plus DTE to increases its .NO release) induces an inhibition of the succinate dependent H2O2 production consistent with a .NO dependent covalent modification. However maximal inhibition of the succinate dependent H2O2 release is obtained in the presence of low GSNO (20–100 μM), but not with SNP. This inhibition appears independent of .NO release since μM GSNO does not affect mitochondrial respiration, or the H2O2 detection systems and its effect is very rapid. Inhibition may be partly due to an increased removal of O2.− since GSNO chemically competes with NBT and cytochrome C in O2.− detection. 相似文献
THE urate-binding α1–α2 globulin has been isolated from human plasma in a highly purified state1. The protein was purified by DEAE-‘Sephadex’, ammonium sulphate precipitation and semi-preparative Polyacrylamide gel electrophoresis. The urate-binding α1–α2 globulin is a rod-shaped glycoprotein, containing 12.1% carbohydrate, with an isoelectric point of 4.6 and a molecular weight of 67,000 ± 4,000. Amino-acid analysis indicated an unknown basic compound which appeared as an extra peak just in front of lysine1. To identify this compound, high voltage paper electrophoresis has been carried out on a plate electrophoresis apparatus in pyridine-acetate buffer pH 3.5. A spot separated out corresponding to ornithine. Amino-acid analysis on a BC-200 automatic analyser (Bio-Cal Instruments Co., West Germany), with a 54 cm column at 55° C and with 0.35 M sodium citrate buffer, pH 5.28, as elution buffer at a flow-rate of 150 ml./h, showed that ornithine was present. The presence of ornithine in the protein hydrolysate was also verified by gas chromatography/mass spectrometry2. 相似文献
While ~30% of the human genome encodes membrane proteins, only a handful of structures of membrane proteins have been resolved to high resolution. Here, we studied the structure of a member of the Cys-loop ligand gated ion channel protein superfamily of receptors, human type A γ2α1β2α1β2 gamma amino butyric acid receptor complex in a lipid bilayer environment. Studying the correlation between the structure and function of the gamma amino butyric acid receptor may enhance our understanding of the molecular basis of ion channel dysfunctions linked with epilepsy, ataxia, migraine, schizophrenia and other neurodegenerative diseases. The structure of human γ2α1β2α1β2 has been modeled based on the X-ray structure of the Caenorhabditis elegans glutamate-gated chloride channel via homology modeling. The template provided the first inhibitory channel structure for the Cys-loop superfamily of ligand-gated ion channels. The only available template structure before this glutamate-gated chloride channel was a cation selective channel which had very low sequence identity with gamma aminobutyric acid receptor. Here, our aim was to study the effect of structural corrections originating from modeling on a more reliable template structure. The homology model was analyzed for structural properties via a 100 ns molecular dynamics (MD) study. Due to the structural shifts and the removal of an open channel potentiator molecule, ivermectin, from the template structure, helical packing changes were observed in the transmembrane segment. Namely removal of ivermectin molecule caused a closure around the Leu 9 position along the ion channel. In terms of the structural shifts, there are three potential disulfide bridges between the M1 and M3 helices of the γ2 and 2 α1 subunits in the model. The effect of these disulfide bridges was investigated via monitoring the differences in root mean square fluctuations (RMSF) of individual amino acids and principal component analysis of the MD trajectory of the two homology models—one with the disulfide bridge and one with protonated Cys residues. In all subunit types, RMSF of the transmembrane domain helices are reduced in the presence of disulfide bridges. Additionally, loop A, loop F and loop C fluctuations were affected in the extracellular domain. In cross-correlation analysis of the trajectory, the two model structures displayed different coupling in between the M2–M3 linker region, protruding from the membrane, and the β1-β2/D loop and cys-loop regions in the extracellular domain. Correlations of the C loop, which collapses directly over the bound ligand molecule, were also affected by differences in the packing of transmembrane helices. Finally, more localized correlations were observed in the transmembrane helices when disulfide bridges were present in the model. The differences observed in this study suggest that dynamic coupling at the interface of extracellular and ion channel domains differs from the coupling introduced by disulfide bridges in the transmembrane region. We hope that this hypothesis will be tested experimentally in the near future. 相似文献
Nine minima were found on the intermolecular potential energy surface for the ternary system HNO3(CH3OH)2 at the MP2/aug-cc-pVDZ level of theory. The cooperative effect, which is a measure of the hydrogen-bonding strength, was probed in these nine conformations of HNO3…(CH3OH)2. The results are discussed here in terms of structures, energetics, infrared vibrational frequencies, and topological parameters. The cooperative effect was observed to be an important contributor to the total interaction energies of the cyclic conformers of HNO3…(CH3OH)2, meaning that it cannot be neglected in simulations in which the pair-additive potential is applied.
Summary Phosphatidylinositol 3-kinase (PI3K) pathway is important for platelet activation. Recent studies showed that PI3K and oscillative
calcium could cross talk to each other and positively regulate integrin α IIbβ3-mediated outside-in signaling. However, the mechanism of this feedback regulation remains to be further characterized. Here
we found that treatments of both PI3K inhibitor wortmannin and P2Y1 inhibitor A3P5P could inhibit granular secretion in platelets.
Additionally, when RGD-substrate adherent platelets were treated with the ADP scavenger apyrase to deplete the granular-released
ADP, their attachments in engaging with substrates became looser and the frequency of calcium oscillation decreased. Since
it is known that ADP stimulates the PI3K and calcium signal primarily through P2Y12 and P2Y1 receptors respectively, our data
indicated that integrin αIIbβ3 downstream PI3K and calcium activation might be not completely coupled to integrin associated signaling complex, but in part
through feedback stimulation by granular released ADP. Our data indicates the important roles of PI3K and granular released
ADP in coordinating the feedback regulations in integrin αIIbβ3-mediated platelet activation. 相似文献
PROSTAGLANDIN (PG) F2αhas antifertility effects in many species1–3 but there are conflicting suggestions as to its mechanism of action. For example, it may cause the degeneration of the corpus luteum by decreasing blood flow in the uteroovarian vein4; alternatively, its action may be due to a hypersecretion of luteinizing hormone (LH) by the pituitary3,5. I have investigated the effects of PGF2α, E2 and E1 on pregnancy in mice and examined the mechanism of action of PGF2α. 相似文献
A new metal complex, Fe(Sal2dienNO3·H2O) (where Sal is salicylaldehyde and dien is diethylenetriamine), has been synthesized and characterized. The interactions
between the Fe(III) complex and calf thymus DNA has been investigated using UV and fluorescence spectra, viscosity, thermal
denaturation, and molecular modeling. The cleavage reaction on plasmid DNA has been monitored by agarose gel electrophoresis.
The experimental results show that the mode of binding of the complex to DNA is classical intercalation and the complex can
cleave pBR322 DNA. 相似文献
Mitochondrial production of H2O2 is low with NAD substrates (glutamate/pyruvate, 3 and 2 mM) (G/P) and increases over ten times upon further addition of succinate,
with the formation of a sigmoidal curve (semimaximal value at 290 μM, maximal H2O2 production at 600 μM succinate). Malate counteracts rapidly the succinate induced increased H2O2 release and moves the succinate dependent H2O2 production curve to the right. Nitric oxide (NO) and carbon monoxide (CO) are cytochrome c oxidase inhibitors which increase
mitochondrial ROS production. Cyanide (CN−) was used to mimic NO and CO. In the presence of G/P and succinate (300 μM), CN− progressively increased the H2O2 release rate, starting at 1.5 μM. The succinate dependent H2O2 production curve was moved to the left by 30 μM CN−. The Vmax was little modified. We conclude that succinate is the controller of mitochondrial H2O2 production, modulated by malate and CN−. We propose that succinate promotes an interaction between Complex II and Complex I, which activates O2− production. 相似文献
A preliminary study on the interaction of G protein (guanine triphosphate binding pro- tein) β1γ2 subunits and their coupled components in cell signal transduction was conducted in vitro. The insect cell lines, Sf9 (Spodoptera frugiperda) and H5 (Trichoplusia ni) were used to express the recombinant protein Gβ1γ2. The cell membrane containing Gβ1γ2 was isolated through affinity chromatography column with Ni-NTA agarose by FPLC method, and the highly purified protein was obtained. The adenylyl cyclase 2 (AC2) activity assay showed that the purified Gβ1γ2 could significantly stimulate AC2 activity. The interaction of β1γ2 subunits of G protein with the cytoplasmic tail of various mammalian adenylyl cyclases was monitored by BIAcore technology using NTA sensor chip, which relies on the phenomenon of surface plasmon resonance (SPR). The experiments showed the direct binding of Gβ1γ2 to the cytoplasmic tail C2 domain of AC2. The specific binding domain of AC2 with Gβ1γ2 was the same as AC2 activity domain which was stimulated by β1γ2. 相似文献
This investigation generated rovibrational energies and spectroscopic constants for systems of CCl4 with Ng (Ng?=?He, Ne, Ar), O2, D2O and ND3 from scattering experimental data, and the results presented are of interest for microwave spectroscopy studies of small halogenated molecules. The rovibrational spectra were obtained through two different approaches (Dunham and DVR) within the improved Lennard Jones (ILJ) model. Spectra were also generated within ordinary Lennard Jones and deviations suggest that the ILJ model should be preferred due to interactions beyond dispersion forces presented in these systems. Data from the literature and additional high level quantum mechanical calculations presented in this work show that these systems should not be considered as van der Waals complexes due to halogen bonding (HB) interactions, and this is especially true for the CCl4–D2O and CCl4–ND3 complexes. The charge displacement from the latter systems are one order of magnitude higher than the values from literature for CCl4 and He, Ne, Ar and O2 systems, and show significant deviations between DFT and Hartree-Fock values not previously reported in the literature. 相似文献
F0F1ATPsynthase is now known to be expressed as a plasma membrane receptor for several extracellular ligands. On hepatocytes,
ecto–F0F1ATPsynthase binds apoA–I and triggers HDL endocytosis concomitant with ATP hydrolysis. Considering that inhibitor protein
IF1 was shown to regulate the hydrolytic activity of ecto–F0F1ATPsynthase and to interact with calmodulin (CaM) in vitro, we investigated the subcellular distributions of IF1, calmodulin (CaM), OSCP and β subunits of F0F1ATPsynthase in HepG2 cells. Using immunofluorescence and Western blotting, we found that around 50% of total cellular IF1 is localized outside mitochondria, a relevant amount of which is associated to the plasma membrane where we also found Ca2+–CaM, OSCP and β. Confocal microscopy showed that IF1 colocalized with Ca2+–CaM on plasma membrane but not in mitochondria, suggesting that Ca2+–CaM may modulate the cell surface availability of IF1 and thus its ability to inhibit ATP hydrolysis by ecto–F0F1ATPsynthase. These observations support a hypothesis that the IF1–Ca2+–CaM complex, forming on plasma membrane, functions in the cellular regulation of HDL endocytosis by hepatocytes. 相似文献
MHC class I molecules are heterotrimeric complexes composed of heavy chain, 2-microglobulin (2m) and short peptide. This trimeric complex is generated in the endoplasmic reticulum (ER), where a peptide loading complex (PLC) facilitates transport from the cytosol and binding of the peptide to the preassembled ER resident heavy chain/2m dimers. Association of mouse MHC class I heavy chain with 2m is characterized by allelic differences in the number and/or positions of amino acid interactions. It is unclear, however, whether all alleles follow common binding patterns with minimal contributions by allele-specific contacts, or whether essential contacts with 2m are different for each allele. While searching for the PLC binding site in the 3 domain of the mouse MHC class I molecule H-2Db, we unexpectedly discovered a site critical for binding mouse, but not human, 2m. Interestingly, amino acids in the corresponding region of another MHC class I heavy chain allele do not make contacts with the mouse 2m. Thus, there are allelic differences in the modes of binding of 2m to the heavy chain of MHC class I. 相似文献
The nucleation, ice crystal shapes and thermodynamic stability of polar stratospheric clouds particles are interesting concerns owing to their implication in the ozone layer destruction. Some of these particles are formed by conformers of H2O, HNO3, and H2SO4. We carried out calculations using density functional theory (DFT) to obtain optimized structures. Several stable trimers are achieved —divided in two groups, one with HNO3 moiety, second with H2SO4 moiety— after pre-optimization at B3LYP/6-31G and subsequently optimization at B3LYP/aug-cc-pVTZ level of theory. For both most stable conformers five H2O molecules are added to their optimized trimers to calculate hydrated geometries. The OH stretching harmonic frequencies are provided for all aggregates. The zero-point energy correction (ZEPC), relative electronic energies (?E), relative reaction Gibbs free energies ?(?G)k-relative, and cooling constant (Kcooling) are reported at three temperatures: 188 K, 195 K, and 210 K. Shapes given in our calculations are compared with various experimental shapes as well as comparisons with their thermo-stabilities.
Graphical Abstract Facet shapes and thermo-stabilities of H2SO4?HNO3 hydrates involved in polar stratospheric clouds. IR spectrum of WNS-1+5W structure and its circular facet
To analyze the influence of the beta-subunit on the kinetic properties of GlyR channel currents, alpha(1)-subunits and alpha(1)beta-subunits were transiently expressed in HEK 293 cells. A piezo dimorph was used for fast application of glycine to outside-out patches. The rise time of activation was dose dependent for both receptors and decreased with increasing glycine concentrations. Subunit composition had no effect on the time course of activation. Coexpression of alpha(1)- and beta-subunits resulted in a significantly lower EC(50) and a reduced slope of the dose-response curve of glycine compared with expression of alpha(1)-subunits alone. For both receptor subtypes, the time course of desensitization was concentration dependent. Desensitization was best fitted with a single time constant at 10-30 micro M, with two at 0.1 mM, and at saturating concentrations (0.3-3 mM) with three time constants. Desensitization of homomeric alpha(1)-receptor channels was significantly slower than that of alpha(1)beta-receptor channels. The time course of current decay after the end of glycine pulses was tested at different pulse durations of 1 mM glycine. It was best fitted with two time constants for both alpha(1) and alpha(1)beta GlyR channels, and increased significantly with increasing pulse duration. 相似文献
The insulin-sensitizing effect of vanadium complexes has been linked to their ability to inhibit protein tyrosine phosphatases
(PTPs). Considering that vanadium complexes may exchange in vivo with amino acids, forming in situ vanadium–amino acid complexes,
we have synthesized and characterized an oxovanadium glutamate complex, Na2[V(IV)O(Glu)2(CH3OH)]H2O (1·H2O). The complex showed potent inhibition against four human PTPs (PTP1B, TCPTP, HePTP, and SHP-1) with IC50 in the 0.21–0.37 μM ranges. Fluorescence titration studies suggest that the complex binds to PTP1B with the formation of
a 2:1 complex. Enzyme kinetics analysis using Lineweaver–Burk plots indicates a typical competitive inhibition mode. 相似文献
Prostaglandins (PGs) are lipid mediators that may play important roles in cancer, immunomodulation, and neurodegeneration. So, the quantitative analysis of PGs will therefore be important in order to understand the natural history of a range of diseases and may be used as a tool in the development of new biotherapeutics. However, such an analysis is problematic because of the small quantities of PGs present in the body. Here, we developed a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-MS)-based analytical method for rapid and easy quantification of the ketone-containing PGs (15d-PGJ2etc.) as a targeted metabolomics platform. The chemical derivatization with Girard’s reagent P (GP) provided a good linearity (R2 > 0.99) between peak area and quantity of 15d-PGJ2 and highly improved sensitivity (limit of quantitation, LOQ: 1.25 pmol on a spot in MALDI plate). Finally, we utilized this method to directly characterize the interaction between peroxisome proliferatoractivated receptor gamma-ligand binding domain (PPARγ-LBD) and 15d-PGJ2. The 15d-PGJ2 was enriched by PPARγ-LBD and also the binding level of the ligand was dropped considerably by the treatment of PPARγ agonist such as rosiglitazone (about 0.61-fold reduction). Taken together, our MALDI-MS-based targeted metabolomics method for ketone-containing PGs may be applicable to elucidate the protein-metabolite interactions and to identify natural ligands for drug candidates. 相似文献
Utilizing first-principles calculations, we studied the electronic and optical properties of C24, C12X6Y6, and X12Y12 fullerenes (X?=?B, Al; Y?=?N, P). These fullerenes are energetically stable, as demonstrated by their negative cohesive energies. The energy gap of C24 may be tuned by doping, and the B12N12 fullerene was found to have the largest energy gap. All of the fullerenes had finite optical gaps, suggesting that they are optical semiconductors, and they strongly absorb UV radiation, so they could be used in UV light protection devices. They could also be used in solar cells and LEDs due to their low reflectivities.
