Terms Of Hydrogen Bonds Research Articles

Insights into Non‐Ideal Behavior of Double Salt Ionic Liquids with Common Cation: Volumetric Behaviour, Molecular Dynamics Simulations and NMR Experiments

AbstractThe designer concept of ionic liquid (ILs) allows combination of different types of cation with anion to manipulate desire sets of physico‐chemical properties. The additional degree of freedom to improve these properties is addition of second IL, i. e. mixture of two pure ILs, known as “Double Salt Ionic Liquids (DSILs)”. Depending on variation in physico chemical properties, DSILs could be ideal or non‐ideal solution. The present study was explores non‐ideal behaviour of three novel combination of imidazolium based DSILs using physico‐chemical properties. The proposed DSILs are homogeneous mixtures of two pure ILs with common cation and two different anions: ethylsulfate and bis(trifluoromethylsulfonyl)imide / trifluoromethanesulfonate / thiocyanate. The densities, ρ and speeds of sound, u for proposed DSILs were determined at different temperatures. The excess molar volumes VmE and excess molar isentropic compressibilities KS,mE were calculated and discussed in view of chemical structures of pure ILs, nature of anions and type of interaction between ions. The VmE were found to be positive for all cases, whereas positive or negative KS,mE were observed for studied DSILs. The behaviour of DSILs was explained by molecular dynamics simulations in terms of interaction energies and hydrogen bonds between components of DSILs as well as 1H NMR results. The results indicate random distribution of anions around imidazolium cation and structural changes during formulation of DSILs.

Vibrational circular dichroism as a probe of solid-state organisation of derivatives of cyclic β-amino acids: Cis- and trans-2-aminocyclobutane-1-carboxylic acid.

Peptide models built from cis- and trans-2-aminocyclobutane-1-carboxylic acids (ACBCs) are studied in the solid phase by combining Fourier-transform infrared spectroscopy (FTIR) absorption spectroscopy, vibrational circular dichroism (VCD), and quantum chemical calculations using density functional theory (DFT). The studied systems are N-tert-butyloxycarbonyl (Boc) derivatives of 2-aminocyclobutanecarboxylic acid (ACBC) benzylamides, namely Boc-(cis-ACBC)-NH-Bn and Boc-(trans-ACBC)-NH-Bn. These two diastereomers show very different VCD signatures and intensities, which of the trans-ACBC derivative being one order of magnitude larger in the region of the ν (CO) stretch. The spectral signature of the cis-ACBC derivative is satisfactorily reproduced by that of the monomer extracted from the solid-state geometry of related ACBC derivatives, which shows that no long-range effects are implicated for this system. In terms of hydrogen bonds, the geometry of this monomer is intermediate between the C6 and C8 structures (exhibiting a 6- or 8-membered cyclic NH⋯O hydrogen bond) previously evidenced in the gas phase. The benzyl group must be in an extended geometry to reproduce satisfactorily the shape of the VCD spectrum in the ν (CO) range, which qualifies VCD as a potential probe of dispersion interaction. In contrast, reproducing the IR and VCD spectrum of the trans-ACBC derivative requires clusters larger than four units, exhibiting strong intermolecular H-bonding patterns. A qualitative agreement is obtained for a tetramer, although the intensity enhancement is not reproduced. These results underline the sensitivity of VCD to the long-range organisation in the crystal.

Reversed phase HPLC with high temperature ethanol/water mobile phases as a green alternative method for the estimation of octanol/water partition coefficients

High temperature ethanol/water was explored as a green eluent in the reversed-phase liquid chromatographic approximation of pure water retention (log kw) and subsequent estimation of the octanol/water partition coefficient (log P) via the Collander equation and the Leave-One-Out method. As part of this work, linear solvation energy relationships were employed to compare the log kw extrapolated systems based on high temperature ethanol/water, ambient acetonitrile/water, and ambient methanol/water mobile phases. Based on the comparisons of the three organic modifiers, high temperature ethanol/water mobile phases were observed to provide the best estimation of log P. This conclusion is based on a high log P correlation of 0.968 R2 and a near unity cos θ value of 0.997 between LSER coefficient vectors of ethanol/water estimated log P and octanol/water log P systems. The method employed in this work, further, provided high correlation for the hydrogen-bonding basicity term between the two systems.

Physicochemical features of short-chain 1-alkyl-3-methylimidazolium bis(trifluoromethylsulfonyl)-imide ionic liquids containing equilibrium water absorbed from air

In the present research we studied ionic liquids of 1-alkyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, [CnMIm][TFSI], where n = 2 (ethyl, C2), 3 (propyl, C3) and 4 (butyl, C4) with small water impurity absorbed though the contact with air. IR spectra, thermodynamic, electrochemical and the bulk properties, such as density and viscosity, were determined by means of FT-IR spectroscopy, conductometry, densimetry, viscosimetry, TG and DSC methods. The influence of temperature, absorbed water and elongation of the cation alkyl chain on the physicochemical properties was studied. It was found that the absorbed water (approximately 0.24–0.25% by weight) is frozen at a temperature from −40.5 to −46.3 °C, has little effect on thermal stability and significantly affects the phase behavior of ionic liquids. The linearly dependence of the density on the temperature was observed. The conductivity increases and the viscosity decreases with increasing temperature according with the VFT equation. Physicochemical properties depend on alkyl chain length, but not linearly, so that C3 is close to the transition between C2 and C4. Such tendency was explained in terms of Van der Waals forces and hydrogen bonds.

Physical Origin of Thermostabilization by a Quadruple Mutation for the Adenosine A2a Receptor in the Active State.

The G protein-coupled receptors (GPCRs) form a large, physiologically important family of membrane proteins and are currently the most attractive targets for drug discovery. We investigate the physical origin of thermostabilization of the adenosine A2a receptor (A2aR) in the active state, which was experimentally achieved by another research group using the four point mutations: L48A, A54L, T65A, and Q89A. The investigation is performed on the basis of our recently developed physics-based free-energy function (FEF), which has been quite successful for the thermodynamics of GPCRs in the inactive state. The experimental condition for solving the wild-type and mutant crystal structures was substantially different from that for comparing their thermostabilities. Therefore, all-atom molecular dynamics simulations are necessitated, which also allows us to account for the structural fluctuations of the membrane protein. We show that the quadruple mutation leads to the enlargement of the solvent-entropy gain upon protein folding. The solvent is formed by hydrocarbon groups constituting nonpolar chains within the lipid bilayer, and the entropy is relevant to the thermal motion of the hydrocarbon groups. From an energetic point of view (e.g., in terms of protein intramolecular hydrogen bonds), the mutation confers no improvement upon the structural stability of A2aR. The reliability of our FEF and the crucial importance of the solvent-entropy effect have thus been demonstrated for a GPCR in the active state. We are now ready to identify thermostabilizing mutations of GPCRs not only in the inactive state but also in the active one.

Decoding Surface Interaction of VIVO Metallodrug Candidates with Lysozyme.

The interaction of metallodrugs with proteins influences their transport, uptake, and mechanism of action. In this study, we present an integrative approach based on spectroscopic (EPR) and computational (docking) tools to elucidate the noncovalent binding modes of various VIVO compounds with lysozyme, a prototypical model of protein receptor. Five VIVO-flavonoid drug candidates formed by quercetin (que), morin (mor), 7,8-dihydroxyflavone (7,8-dhf), chrysin (chr), and 5-hydroxyflavone (5-hf)-effective against several osteosarcoma cell lines-and two benchmark VIVO species of acetylacetone (acac) and catechol (cat) are evaluated. The results show a gradual variation of the EPR spectra at room temperature, which is associated with the strength of the interaction between the square pyramidal complexes [VOL2] and the surface residues of lysozyme. The qualitative strength of the interaction from EPR is [VO(que)2]2- ≈ [VO(mor)2] > [VO(7,8-dhf)2]2- > [VO(chr)2] ≈ [VO(5-hf)2] > [VO(acac)2] ≈ [VO(cat)2]2-. This observation is compared with protein- ligand docking calculations with GOLD software examining the GoldScore scoring function ( F), for which hydrogen bond and van der Waals contact terms have been optimized to account for the surface interaction. The best predicted binding modes display an energy trend in good agreement with the EPR spectroscopy. Computation indicates that the strength of the interaction can be predicted by the Fmax value and depends on the number of OH or CO groups of the ligands that can interact with different sites on the protein surface and, more particularly, with those in the vicinity of the active site of the enzyme. The interaction strength determines the type of signal revealed ( rigid limit, slow tumbling, or isotropic) in the EPR spectra. Spectroscopic and computational results also suggest that there are several sites with comparable binding energy, with the V complexes distributing among them in a bound state and in aqueous solution in an unbound state. This kind of study and analysis could be generalized to determine the noncovalent binding modes of a generic metal species with a generic protein.

Linear solvation energy relationship (LSER) characterization of the normal phase retention mechanism on hypercrosslinked polystyrenes

Linear solvation energy relationships (LSERs) were applied to retention on hypercrosslinked polystyrene on silica (HC-Tol) to elucidate the type and relative importance of molecular interactions between model solutes and the HC-Tol stationary phase. Classical amino phase and another hypercrosslinked phase (5-HGN) were used as reference columns. On both the HC-Tol and amino, polar interactions predominate and contribute to retention. Solute volume V has no impact on retention on the amino column, while V has a slightly negative influence on retention for the HC-Tol column. The differences in coefficient v between the amino and the HC-Tol columns might explain why the HC-Tol is capable of group-type separations. 5-HGN phase has smaller a and b values compared to HC-Tol, which means that 5-HGN is not as basic or acidic in terms of hydrogen bonds as is HC-Tol. This suggests that the hydrogen bonding character of the HC-Tol phase arises from its silica substrate.

Interactions of 2'-O-methyl oligoribonucleotides with the RNA models of the 30S subunit A-site.

Synthetic oligonucleotides targeting functional regions of the prokaryotic rRNA could be promising antimicrobial agents. Indeed, such oligonucleotides were proven to inhibit bacterial growth. 2’-O-methylated (2’-O-Me) oligoribonucleotides with a sequence complementary to the decoding site in 16S rRNA were reported as inhibitors of bacterial translation. However, the binding mode and structures of the formed complexes, as well as the level of selectivity of the oligonucleotides between the prokaryotic and eukaryotic target, were not determined. We have analyzed three 2’-O-Me oligoribonucleotides designed to hybridize with the models of the prokaryotic rRNA containing two neighboring aminoglycoside binding pockets. One pocket is the paromomycin/kanamycin binding site corresponding to the decoding site in the small ribosomal subunit and the other one is the close-by hygromycin B binding site whose dynamics has not been previously reported. Molecular dynamics (MD) simulations, as well as isothermal titration calorimetry, gel electrophoresis and spectroscopic studies have shown that the eukaryotic rRNA model is less conformationally stable (in terms of hydrogen bonds and stacking interactions) than the corresponding prokaryotic one. In MD simulations of the eukaryotic construct, the nucleotide U1498, which plays an important role in correct positioning of mRNA during translation, is flexible and spontaneously flips out into the solvent. In solution studies, the 2’-O-Me oligoribonucleotides did not interact with the double stranded rRNA models but all formed stable complexes with the single-stranded prokaryotic target. 2’-O-Me oligoribonucleotides with one and two mismatches bound less tightly to the eukaryotic target. This shows that at least three mismatches between the 2’-O-Me oligoribonucleotide and eukaryotic rRNA are required to ensure target selectivity. The results also suggest that, in the ribosome environment, the strand invasion is the preferred binding mode of 2’-O-Me oligoribonucleotides targeting the aminoglycoside binding sites in 16S rRNA.

Reverse-selective behavior of room temperature ionic liquid based membranes for natural gas processing

This experimental study explores the reverse-selective potential of room temperature ionic liquid (RTIL) based membranes by lowering the solubility of the non-condensing gases, N2 and CH4. Particular attention is given to the reverse-selective behavior in the propane/methane, propane/nitrogen, and n-butane/methane separations. For this purpose, a series of experiments were conducted in a batch gas permeance system. The permeances of the above-mentioned gases were obtained using polyvinylidene fluoride (PVDF) as the porous liquid stabilizing support and [emim][Tf2N], [emim][BF4], [emim][TfO], [emim][DCA], [emim][SCN], and [bmim][NO3] as the stabilized RTILs. The permeance of CH4 and N2 were investigated in terms of hydrogen bond accepting ability of the RTIL, as an indication of the gas/RTIL solution nonideality. The results show that an increase in the solution nonideality leads to a decrease in the CH4 and N2 permeances. This decrease in permeances resulted in RTIL-membrane selectivities for the propane separations that are greater than polymer membrane literature values. The reverse-selective behavior decreases with an increase in the viscosity of the RTILs, which may be due to a shift in the dominate transmission mechanism from solubility to diffusion.

Syntheses and structure characterization of ten acid-base hybrid crystals based on N-containing aromatic brønsted bases and mineral acids

Cocrystallization of the aromatic brønsted bases with a series of mineral acids gave a total of ten hybrid salts with the compositions: (2-methylquinoline)2: (hydrochloride acid): 3H2O [(HL1)+. (L1)·· (Cl-) · (H2O)3] (1), (6-bromobenzo[d]thiazol-2-amine): (hydrochloride acid) [(HL2)+. (Cl-)] (2), (6-bromobenzo[d]thiazol-2-amine): (nitric acid) [(HL2)+. (NO3-)] (3), (6-bromobenzo[d]thiazol-2-amine): (sulfuric acid) [(HL2)+ · (HSO4)-] (4), (6-bromobenzo[d]thiazol-2-amine): (phosphoric acid) [(HL2)+ · (H2PO4)-] (5), (5,7-dimethyl-1,8-naphthyridine-2-amine): (hydrochloride acid): 3H2O [(HL3)+ · (Cl-) (H2O)3] (6), (5,7-dimethyl-1,8-naphthyridine-2-amine): (hydrobromic acid): CH3OH [(HL3)+ · (Br)- · CH3OH] (7), (5,7-dimethyl-1,8-naphthyridine-2-amine): (sulfuric acid): H2O [(HL3)+ · (HSO4)- · H2O] (8), (2-aminophenol): (phosphoric acid) [(HL4)+ · (H2PO4)-] (9), and (2-amino-4-chlorophenol): (phosphoric acid) [(HL5)+ · (H2PO4)-] (10). The ten salts have been characterized by X-ray diffraction analysis, IR, and elemental analysis, and the melting points of all the salts were also reported. And their structural and supramolecular aspects are fully analyzed.The result reveals that among the ten investigated crystals the ring N of the heterocycle or the NH2 in the aminophenol are protonated when the acids are deprotonated, and the crystal packing is interpreted in terms of the strong charge-assisted classical hydrogen bonds between the NH+/NH3+ and deprotonated acidic groups. Further analysis of the crystal packing of the salts indicated that a different family of additional CHO, CHCl, CH3N, CH3O, CHBr, CH3Br, BrCl, ClS, OS, OO, BrS, HH, and π-π associations contribute to the stabilization and expansion of the total high-dimensional frameworks. For the coexistence of the various weak nonbonding interactions these structures adopted homo or hetero supramolecular synthons or both. Some classical supramolecular synthons, such as R22(8), R42(8), R43(10) and R44(12), usually observed in the organic solids, were again shown to be involved in constructing most of these H-bonding networks.

IN VITRO AND IN SILICO EVALUATION OF XANTHINE OXIDASE INHIBITORY ACTIVITY OF QUERCETIN CONTAINED IN SONCHUS ARVENSIS LEAF EXTRACT

Objective: The aim of the present study was to examine the inhibiting effects of quercetin contained in Sonchusarvensis leaf extract on the activity of xanthine oxidase, an essential enzyme for uric acid synthesis.Methods: Activity test was conducted in vitro by measuring the activity of xanthine oxidase using UV spectrophotometry and in silico by determining the interaction of quercetin and allopurinol (as comparation drug) with xanthine oxidase enzyme in terms of hydrogen bonds and binding free energy. Docking simulations were performed by Autodock4.2 package.Results: The active fraction, using the solvent n-hexane, ethyl acetate and water, tested the inhibitory activity of the xanthine oxidase enzyme in vitro obtained respectively IC50 of 263.19, 16.20 and 141.80 μg/ml. Isolates with highest activity identified as quercetin. The xanthine oxidase enzyme inhibitory activity insilico by molecular docking showed quercetin has free energy binding ˗7.71 kcal/mol, more negative than that of allopurinol ˗5.63 kcal/mol.Conclusion: This shows the affinity of quercetin stronger than that of allopurinol; so that it can be predicted that quercetin was more potential to inhibit xanthine oxidase enzyme activity. Thus the extract of the S. arvensis leaves containing the active compound quercetin was a potential use as antihyperuricemia.

Synthesis, docking, and evaluation of novel thiazoles for potent antidiabetic activity

In this study, a series of novel substituted pyrazoles containing indole and thiazole motifs were synthesized and evaluated for their antihyperglycemic activity against α-amylase and α-glucosidase enzymes. Among them, 2-(5-(1H-indol-3-yl)-3-phenyl-1H-pyrazol-1-yl)-4-(4-bromo phenyl) thiazole (3f) was identified as the best antihyperglycemic activity (IC50 = 236.1 µg/mL) in comparison with the standard drug (acarbose, IC50 = 171.8 µg/mL). Through reverse screening, glucocorticoid receptor (1NHZ) was identified as the best target and molecular docking studies was performed to understand the interaction of the molecules to the active sites of 1NHZ. The docking study was then conducted against the enzymes (α-amylase (4X9Y) and α-glucosidase (2QMJ)) used in the in vitro studies. A molecular dynamic simulation experiment was conducted to analyze the behavior of the docked complex. The analysis confirmed the stability of the docked complex in terms of energy and hydrogen bonds. In vitro and in silico evaluations thus generate an interesting insight toward exploring heteroaryl substituted pyrazoles as potent therapeutic antidiabetic agents.

Osmotic Second Virial Coefficients of Aqueous Solutions from Two-Component Equations of State.

Osmotic second virial coefficients in dilute aqueous solutions of small nonpolar solutes are calculated from three different two-component equations of state. The solutes are five noble gases, four diatomics, and six hydrocarbons in the range C1-C4. The equations of state are modified versions of the van der Waals, Redlich-Kwong, and Peng-Robinson equations, with an added hydrogen-bonding term for the solvent water. The parameters in the resulting equations of state are assigned so as to reproduce the experimental values and temperature dependence of the density, vapor pressure, and compressibility of the solvent, the gas-phase second virial coefficient of the pure solute, the solubility and partial molecular volume of the solute, and earlier estimates of the solutes' molecular radii. For all 15 solutes, the calculations are done for 298.15 K, whereas for CH4, C2H6, and C3H8 in particular, they are also done as functions of temperature over the full range 278.15-348.15 K. The calculated osmotic virial coefficients are compared with earlier calculations of these coefficients for these solutes and also with the results derived from earlier computer simulations of model aqueous solutions of methane. They are also compared with the experimental gas-phase second virial coefficients of the pure gaseous solutes to determine the effect the mediation of the solvent has on the resulting solute-solute interactions in the solution.

Hydrogen-Bonding Polarizable Intermolecular Potential Model for Water.

A polarizable intermolecular potential model with short-range directional hydrogen-bonding interactions was developed for water. The model has a rigid geometry, with bond lengths and angles set to experimental gas-phase values. Dispersion interactions are represented by the Buckingham potential assigned to the oxygen atom, whereas electrostatic interactions are modeled by Gaussian charges. Polarization is handled by a Drude oscillator site, using a negative Gaussian charge attached to the oxygen atom by a harmonic spring. An explicit hydrogen-bonding term is included in the model to account for the effects of charge transfer. The model parameters were optimized to density, configurational energy, pair correlation function, and the dielectric constant of water under ambient conditions, as well as the minimum gas-phase dimer energy. Molecular dynamics and Gibbs ensemble Monte Carlo simulations were performed to evaluate the new model with respect to the thermodynamic and transport properties over a wide range of temperature and pressure conditions. Good agreement between model predictions and experimental data was found for most of the properties studied. The new model yields better performance relative to the majority of existing models and outperforms the BK3 model, which is one of the best polarizable models, for vapor-liquid equilibrium properties, whereas the new model is not better than the BK3 model for representation of other properties. The model can be efficiently simulated with the thermalized Drude oscillator algorithm, resulting in computational costs only 3 times higher than those of the nonpolarizable TIP4P/2005 model, whereas having significantly improved properties. Because it involves only a single Drude oscillator site, the new model is significantly faster than polarizable models with multiple sites. With the explicit inclusion of hydrogen-bond interactions, the model may provide a better description of the phase behavior of aqueous mixtures.

Poly(ethylene glycol)–polyhedral oligomeric silsesquioxane as a novel plasticizer and thermal stabilizer for poly(vinyl chloride) nanocomposites

AbstractThe plasticizing and thermostabilizing effect of poly(ethylene glycol)–polyhedral oligomeric silsesquioxane (PEG‐POSS) on poly(vinyl chloride) (PVC) is discussed thoroughly in this work. As PEG‐POSS content increases, PVC becomes more flexible and the decomposition temperature of PVC increases slightly. Meanwhile, the temperature of maximum HCl emission is elevated from 265.3 °C in neat PVC to 285.7 °C in PVC nanocomposites, with the peak intensity of HCl emission decreased by 30.8%, and a new lower intensity of HCl emission peak appearing at much higher temperature (around 370 °C), which is in accordance with the maximum degradation temperature of PEG‐POSS. Thereby, a possible dehydrochlorination mechanism is suggested according to the fact that the electron donor effect of ether groups would stabilize the CCl bonds by means of more electron cloud stacked in those bonds, which agrees with Fourier transform infrared and X‐ray photoelectron spectroscopy experiments in terms of hydrogen bonds. © 2016 Society of Chemical Industry

Six hydrogen-bonded supramolecular frameworks assembled from organic acids and p-dimethylaminobenzaldehyde

Cocrystallization of the commonly available organic compound, p-dimethylaminobenzaldehyde, with a series of organic acids gave a total of six molecular adducts with the compositions: p-dimethylaminobenzaldehyde : (3,5-dinitrosalicylic acid) [(L) · (Hdsa), Hdsa = 3,5-dinitrosalicylic acid] (1), p-dimethylaminobenzaldehyde : (3-nitrophthalic acid) [(L) · (3-H2npa), 3-H2npa = 3-nitrophthalic acid] (2), p-dimethylaminobenzaldehyde : (4-nitrophthalic acid) [(L) · (4-H2npa), 4-H2npa = 4-nitrophthalic acid] (3), p-dimethylaminobenzaldehyde : (1,5-naphthalenedisulfonic acid) : (NH3)2 [NH4 · (HL) · (nds2−) · NH3, nds− = 1,5-naphthalenedisulfonate] (4), p-dimethylaminobenzaldehyde : (oxalic acid)0.5 [(L) · (H2oa)0.5, H2oa = oxalic acid] (5), and p-dimethylaminobenzaldehyde : (fumaric acid)0.5 [(L) · (H2fum)0.5, H2fum = fumaric acid] (6). The six molecular adducts have been characterized by X-ray diffraction technique, IR, and elemental analysis, and the melting points of all adducts were also reported. And their structural and supramolecular aspects are fully analyzed. Of the six adducts, only 4 is an organic salt and the other five are cocrystals.The crystal packing is interpreted in terms of the strong classical hydrogen bonds as well as other weak non-classical hydrogen bonds. The different families of non-covalent bonds contribute to the stabilization and expansion of the total high-dimensional (2D–3D) frameworks.

Abstract B160: Esculetin induces antiproliferative and apoptotic response in PANC-1 cells by directly binding to Keap1

Abstract Esculetin, a coumarine derivative, has been reported to inhibit growth of various human cancer cells. However, the targets to which esculetin binds and the possible mechanism for its cytotoxicity in cancer cells remain to be elucidated. Herein the effect of esculetin on PANC-1 cells and its mechanism of action were evaluated. Treatment with 100 μM esculetin resulted in significant growth inhibition in PANC-1 cells with G1-phase cell cycle arrest within 12 hour. Induction of apoptosis was confirmed in cells on 24 hour treatment with 100μM esculetin by flow cytometric analysis of apoptotic marker annexin V and temporal increase in the active form of caspase 3, 8 and 9. Apoptosis was found to be associated with loss of mitochondial membrane potential analyzed through measurement of fluorescence by JC-1 dye and increase in cytosolic cytochrome-C levels. A notable decrease in intracellular ROS observed in PANC-1 cells on esculetin treatment, propelled focus on regulation of Nrf2, a major antioxidant response regulator. Keap1 protein sequesters Nrf2 transcription factor in the cytoplasm and promotes its degradation. Direct inhibition of Nrf2-Keap1 interaction has recently emerged as an attractive strategy for cancer treatment. Co-immunoprecipation assays carried out on both Nrf2 and Keap1 revealed a loss of interaction between the two on esculetin treatment. Nuclear accumulation of Nrf2 observed with confocal microsopy and western blot and upregulation of expression of Nrf2 regulated gene NQO1 observed with qPCR further supported the activation of Nrf2. To account for the loss of Nrf2-Keap1 interaction on esculetin treatment, direct binding potential between esculetin and keap1 was checked. Molecular docking studies predicted that esculetin displayed significant interactions in terms of hydrogen bond, π-cationic and π-π aromatic interactions with the subpocket P1 and P3 of the Keap1 receptor to provide inhibitory profile. The direct binding of esculetin with keap1 was then confirmed by pull down assay using esculetin conjugated sepharose beads. A recently established implication of Nrf2 activation is its antagonistic effect on NF-κB, an anti-apoptotic transcription factor that promotes cell cycle progression. Here too, p65-NF-κB protein levels were found to decrease on Nrf2 activation in a temporal fashion on esculetin treatment on PANC-1 cells. Our findings thus suggest that esculetin binds to Keap1 and thereby promotes nuclear accumulation of Nrf2 in PANC-1 cells that possibly induces antiproliferative and apoptotic response by attenuating NF-κB. Citation Format: Rashi Arora, Sharad Sawney, Vikas Saini, Manisha Tiwari, Daman Saluja. Esculetin induces antiproliferative and apoptotic response in PANC-1 cells by directly binding to Keap1. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B160.

Probing the Huntingtin 1-17 Membrane Anchor on a Phospholipid Bilayer by Using All-Atom Simulations

Mislocalization and aggregation of the huntingtin protein are related to Huntington’s disease. Its first exon—more specifically the first 17 amino acids (Htt17)—is crucial for the physiological and pathological functions of huntingtin. It regulates huntingtin’s activity through posttranslational modifications and serves as an anchor to membrane-containing organelles of the cell. Recently, structure and orientation of the Htt17 membrane anchor were determined using a combined solution and solid-state NMR approach. This prompted us to refine this model by investigating the dynamics and thermodynamics of this membrane anchor on a POPC bilayer using all-atom, explicit solvent molecular dynamics and Hamiltonian replica exchange. Our simulations are combined with various experimental measurements to generate a high-resolution atomistic model for the huntingtin Htt17 membrane anchor on a POPC bilayer. More precisely, we observe that the single α-helix structure is more stable in the phospholipid membrane than the NMR model obtained in the presence of dodecylphosphocholine detergent micelles. The resulting Htt17 monomer has its hydrophobic plane oriented parallel to the bilayer surface. Our results further unveil the key residues interacting with the membrane in terms of hydrogen bonds, salt-bridges, and nonpolar contributions. We also observe that Htt17 equilibrates at a well-defined insertion depth and that it perturbs the physical properties—order parameter, thickness, and area per lipid—of the bilayer in a manner that could favor its dimerization. Overall, our observations reinforce and refine the NMR measurements on the Htt17 membrane anchor segment of huntingtin that is of fundamental importance to its biological functions.

A DFT approach to the charge transport related properties in columnar stacked π-conjugated N-heterocycle cores including electron donor and acceptor units.

We present a density functional theory (DFT) study on charge-transport related properties in a series of discotic systems based on 1,3,5-triazine and tris[1,2,4]triazolo[1,3,5]triazine central cores as electron acceptor units, and phenyl-thiophene and N-carbazolyl-thiophene segments as electron donor units. The presence of both electron donor and acceptor moieties in the π-conjugated core could lead to new discotic liquid crystal (DLC) materials which are predicted to display ambipolar charge transport behavior in such a way that electrons could move through the central part of the next cores while holes mainly do through the peripheral groups. A significant increase in hole mobility when N-carbazolyl is present as an electron donor unit in the peripheral region is predicted. In addition, a detailed topological analysis of the electron charge density within the framework provided by Quantum Theory of Atoms in Molecules (QTAIM) has been performed in order to characterize intra- and intermolecular interactions in terms of hydrogen bonds and/or π···π stacking which contribute to the stabilization of the columnar stack and the helical self-assembly at the molecular scale.

Local water dynamics around antifreeze protein residues in the presence of osmolytes: the importance of hydroxyl and disaccharide groups.

Antifreeze proteins (AFP) and antifreeze glycoproteins (AFGP) are synthesized by various organisms to enable their cells to survive low temperature environments like in the polar regions. The presence of antifreeze proteins leads to a temperature difference between the melting and freezing point of the solution known as thermal hysteresis. It is nowadays common knowledge that the antifreeze activity of AFPs is mainly determined by a short-range effect which includes a direct binding to the ice phase. Recently, experimental findings also revealed a long-range effect which implies a significant retardation of the water dynamics to facilitate the ice-binding process specifically for AFGPs. The aim of this work is to examine the dynamics of water molecules around different antifreeze protein residues by using atomistic molecular dynamics simulations. A prototype of AFP from antarctic notothenioids with the main subunit alanine-alanine-threonine (AAT) and a mutant (polyalanine) together with the residues of an antifreeze glycoprotein (AFGP) were simulated and compared with respect to their influence on the local water shell. The analysis of the water hydrogen bond characteristics and the dipolar relaxation times reveals a strong retardation effect of the water dynamics around the AFGP prototype. Our numerical results reveal the significant importance of polar units like threonine and disaccharides for the direct binding of water molecules in terms of hydrogen bonds and a significant retardation of water dynamics. In addition, a considerable change of the hydration dynamics is additionally observed in the presence of osmolytes like urea and hydroxyectoine. Our findings indicate that this effect is even more pronounced in the presence of kosmotropic osmolytes.