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Molecular Modeling (molecular + modeling)
Terms modified by Molecular Modeling Selected AbstractsComparison of Cyclodextrin-Dipeptide Inclusion Complexes in the Absence and Presence of Urea by Means of Capillary Electrophoresis, Nuclear Magnetic Resonance and Molecular ModelingEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 18 2007Benjamin Waibel Abstract The use of capillary electrophoresis (CE) modified with cyclodextrin (CD) for the separation of stereoisomers of peptides is well established. To increase the solubility of ,-CD, urea is often added to the buffer which may influence the complexation of a CD with a guest molecule. The aim of the present study was to investigate the influence of urea on the complexation between dipeptides and ,-CD using Ala-Phe and Ala-Tyr as model compounds. For this purpose three different analytical methods were employed: capillary electrophoresis (CE), 1H-NMR spectroscopy and molecular dynamics simulations (MD). Electropherograms of the peptide enantiomers were different in the presence and absence of urea. For example, at pH,2.5 in the absence of urea the enantiomers of Ala-Tyr are not separated in contrast to the use of buffers containing urea. Applying "complexation-induced chemical shift (CICS)" in NMR spectroscopy and rotating frame Overhauser enhancement spectroscopy (ROESY) revealed differences in the complexation of the peptide enantiomers by ,-CD in the absence and presence of urea suggesting the stabilization of the complex through the phenolic hydroxyl group of tyrosine. MD simulations for different complexes were carried out with consideration of both water and urea molecules in solution. Simulations were performed for 1 ns. In conclusion, NMR spectroscopy and MD methods help to understand the structure of peptide-CD complexes and the separation and migration behavior in CE. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007) [source] MaSK: A visualization tool for teaching and research in computational chemistryINTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, Issue 1 2009Yevgeniy Podolyan Abstract The number of researchers using computational chemistry tools is growing every year. There are multiple programs used for calculation of various molecular and electronic properties such as optimized geometry, energy, vibrational spectra, and so forth. Another set of programs is used for the visualization of these properties. However, such programs are either too complex for a beginner or too simple for an intermediate user for everyday use. Molecular Modeling and Simulation Kit (MaSK) is designed to fill this gap by presenting an easy-to-use intuitive interface to quantum chemical programs such as GAMESS and Gaussian with an array of advanced tools. The program can be used as a postprocessor to visualize calculated properties or as a preprocessor to prepare the input files for quantum chemical programs. In addition, some properties such as the surfaces of molecular orbitals, electron and spin densities, and molecular electrostatic potentials are actually calculated by MaSK. If MaSK is combined with PC GAMESS, the preparation of the input, running of the calculations, and the display of the results can all be done without leaving the program's interface. © 2008 Wiley Periodicals, Inc. Int J Quantum Chem, 2009 [source] Molecular Modeling Of The Aldose Reductase-Inhibitor Complex Based On The X-Ray Crystal Structure And Studies With Single-Site- Directed MutantsJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 2 2000S.B. Singh Aldose reductase (AR) has been implicated in the etiology of the secondary complications of diabetes. This enzyme catalyzes the reduction of glucose to sorbitol using nicotinamide adenine dinucleotide phosphate as an essential cofactor. AR has been localized at the sites of tissue damage, and inhibitors of this enzyme prevent the development of neuropathy, nephropathy, retinopathy, and cataract formation in animal models of diabetes. The crystal structure of AR complexed with zopolrestat, a potent inhibitor of AR, has been described. (1) We have generated a model of the AR-inhibitor complex based on the reported C alpha coordinates of the protein and results of a structure-activity relationship study using four structurally distinct classes of inhibitors, recombinant human AR, and four single-site-directed mutants of this enzyme. The effects of the site-directed mutations on residues within the active site of the enzyme were evaluated by average interaction energy calculations and by calculations of carbon atom surface area changes. These values correlated well with the IC50 values for zopolrestat with the wildtype and mutant enzymes, validating the model. On the basis of the zopolrestat-binding model, we have proposed binding models for 10 other AR inhibitors. Our models have enabled us to gain a qualitative understanding of the binding domains of the enzyme and how different inhibitors impact the size and shape of the binding site. [source] Generation of Selective TACE Inhibitors: Ligand and Structure Based Molecular Modeling, Virtual Screening, Counter Pharmacophore Screening to Get Selective MoleculesMOLECULAR INFORMATICS, Issue 11-12 2009Malkeet, Singh Bahia Abstract This study describes the ligand based as well as structure based molecular modeling and virtual screening of selective tumor necrosis factor-, converting enzyme (TACE) inhibitors. In ligand based molecular modeling, two statistically reliable pharmacophore models HypoA1 and HypoB1 were generated using a same training set of 22,molecules. HypoA1,consists of two hydrogen bond acceptor and three hydrophobic groups whereas HypoB1 consists of one hydrogen bond donor, one ring aromatic and three hydrophobic groups. Virtual screening was performed with both models in in-house database of 1.2,million molecules. To remove non selective hits from screened molecules, a counter pharmacophore was generated using inhibitors of MMP-1, an important enzyme involved in musculoskeletal degradation. In structure based molecular modeling, docking analysis was performed to explore the important interactions between ligands and protein. On comparison, HypoA1 and HypoB1 were found to be complementing with results of docking analysis suggesting high reliability of both models for their use in virtual screening/designing of new molecules. [source] Molecular Modeling and Receptor-Dependent (RD) 3D-QSAR Approach to a Set of Antituberculosis DerivativesMOLECULAR INFORMATICS, Issue 11-12 2009Fernanda, Kerly, Mesquita Pasqualoto Abstract In this study, receptor-dependent (RD) 3D-QSAR models were built for a set of thirty-seven isoniazid derivatives bound to the enoyl-acp reductase from M. tuberculosis, called InhA (PDB entry code 1zid). Ligand-receptor (L-R) molecular dynamics (MD) simulations [500,000 steps; the step size was 0.001,ps (1,fs)] were carried out at 310,K (biological assay temperature). The hypothesized active conformations resulting from a previously reported receptor-independent (IR) 4D-QSAR analysis were used as the molecular geometries of each ligand in this structure-based L-R binding research. The dependent variable is the reported MIC values against M. tuberculosis var. bovis. The independent variables (descriptors) are energy terms of a modified first-generation AMBER force field combined with a hydration shell aqueous solvation model. Genetic function approximation (GFA) formalism and partial least squares (PLS) regression were employed as the fitting functions to develop 3D-QSAR models. The bound ligand solvation energy, the sum of electrostatic and hydrogen bonding energies of the unbound ligand, the bending energy of the unbound ligand, the electrostatic intermolecular L-R energy, and the change in hydrogen bonding energy upon binding were found as important energy contributions to the binding process. The 3D-QSAR model at 310,K has good internal and external predictability and may be regarded as representative of the binding process of ligands to InhA. [source] Molecular Modeling of Meta II RhodopsinMOLECULAR INFORMATICS, Issue 2 2006lusarz Abstract A model believed to be representative for activated class A G protein-coupled receptors is proposed. It consists of rhodopsin and the transducin , C-terminal peptide [Gt,(338,350)] docked to it. The model utilizes the resolved interactions/distances, found to be essential in the activated rhodopsin (RD*) and the structure of Gt,(338,350) that is known to stabilize RD*. Long-term molecular dynamics (14.8,ns) in fully hydrated lipid bilayer model is applied to the system to refine and verify conformational changes in rhodopsin itself and the structure of the complex. A concomitant role of Gt, and Gt, C-termini in stabilizing RD* could possibly be resolved assuming a receptor dimer as a requisite for G protein activation. [source] Molecular Modeling in Crystal Engineering for Processing of Energetic MaterialsPROPELLANTS, EXPLOSIVES, PYROTECHNICS, Issue 6 2003Stéphane Bénazet Abstract Nowadays molecular modeling is available to explain molecular phenomena. This approach helps to compute crystal surface property effects that can be used both for morphology studies and optimal design of "bonding agents" to prevent filler-binder detachment. The principles of crystal growth and of interaction energy computing have been applied to Hexanitrohexaazaisowurtzitane (HNIW). Crystallization experiments validate our calculations. Three families of additives of crystal growth are distinguished: the retarding (and inhibitor) agents, the promoters and finally the "tailor-mades". Retarding and inhibitor agents are the most interesting one to find bonding agents. HNIW is used to present our methodology, but engineering using molecular modeling could be generalized to other fillers. [source] Molecular Modeling, Total Synthesis, and Biological Evaluations of C9-Deoxy Bryostatin,1,ANGEWANDTE CHEMIE, Issue 27 2010Ohne OH: Die Titelverbindung 1 wurde hergestellt und auf ihre biologische Funktion geprüft. Rechnungen zufolge geht Bryostatin,1 über seine C9-OH-Gruppe eine H-Brücke mit der C1-Domäne der Proteinkinase,C,, ein. Trotz Fehlens dieser H-Brücke im Fall von 1 zeigte dieses eine Bryostatin-ähnliche biologische Wirkung in vier Assays unter Verwendung von U937-Leukämiezellen oder LNCaP-Prostatazellen. [source] Elucidation of the Structure and Intermolecular Interactions of a Reversible Cyclic-Peptide Inhibitor of the Proteasome by NMR Spectroscopy and Molecular Modeling,ANGEWANDTE CHEMIE, Issue 23 2010Benjamin Stauch Komplexe Betrachtungen: Das Proteasom spielt bei Krankheiten eine entscheidende Rolle und reizt daher als Therapieziel. Ein Strukturmodell (siehe Bild) des Proteasoms im Komplex mit Argyrin, einem cyclischen Heptapeptid mit Antitumorwirkung, liefert eine Erklärung für die hohe biologische Aktivität dieses Naturstoffs. Die bekannten Struktur-Aktivitäts-Beziehungen dieses Wirkstoffs werden auf der Grundlage dieses Modells diskutiert. [source] Peter Comba, Trevor W Hambley and Bodo Martin Molecular Modeling of Inorganic Compounds (3rd Edition) Wiley-VCH, 2009, 344 pp. (hardback) ISBN 978-3-527-31799-8APPLIED ORGANOMETALLIC CHEMISTRY, Issue 7 2010Alan Hinchliffe No abstract is available for this article. [source] Enantioselective Proteins: Selection, Binding Studies and Molecular Modeling of Antibodies with Affinity towards Hydrophobic BINOL DerivativesCHEMBIOCHEM, Issue 16 2007Brian Schou Rasmussen Dr. Abstract In this paper, the initial steps towards the design of novel artificial metalloenzymes that exploit proteins as a second coordination sphere for traditional metal,ligand catalysis are described. Phage display was employed to select and study antibody fragments capable of recognizing hydrophobic BINOL derivatives designed to mimic BINAP, a widely used ligand in asymmetric metal-catalyzed reactions. The binding affinities of the selected antibodies towards a series of haptens were evaluated by using ELISA assays. A homology model of one of the most selective antibodies was constructed, and a computer-assisted ligand-docking study was carried out to elucidate the binding of the hapten. It was shown that, due to the hydrophobic nature of the haptens, a higher level of theoretical treatment was required to identify the correct binding modes. A small selection of the antibodies was found to discriminate between enantiomers and small structural modifications of the BINOL derivatives. The selectivities arise from hydrophobic interactions, and we propose that the identified set of antibodies provides a foundation for a novel route to artificial metalloenzymes. [source] Mutational Studies Confirm the Catalytic Triad in the Human Selenoenzyme Thioredoxin Reductase Predicted by Molecular ModelingCHEMBIOCHEM, Issue 11 2006Stephan Gromer Dr. Three's company. Site-directed mutagenesis of Glu477 of the human thioredoxin reductase (see figure) to glutamine, alanine, or lysine led to a significant drop in enzymatic activity. This study reinforces previous theoretical calculations which suggested that a swapping catalytic triad exists in the active site of this enzyme. [source] Molecular Modeling Suggests Conformational Scaffolds Specifically Targeting Five Subtypes of Somatostatin ReceptorsCHEMICAL BIOLOGY & DRUG DESIGN, Issue 3 2007Gregory V. Nikiforovich Several analogs of somatostatin with conformational constraints in their peptide backbones have been modeled to determine energetically feasible conformations. Comparison of low-energy backbone structures of these peptides suggested unique conformations of the central Phe/Alai -D-Trpi+1 -Lysi+2 -Thri+3 fragment characteristic for specific interactions of somatostatin with each of the five distinct subtypes of somatostatin receptors (SSTRs). The conformations obtained were in good agreement with experimental data obtained earlier by NMR measurements and/or X-ray crystallography. The results help rationalize experimental observations on the specificity of binding of various somatostatin analogs with different subtypes of the SSTRs. They also serve as templates for the design of conformationally constrained non-peptide scaffolds that effectively and selectively interact with different subtypes of SSTRs. Such scaffolds can be convenient carriers of radiolabels and near-infrared labels in specific agents for imaging tumors expressing different SSTR subtypes. [source] The Study of Molecular Modeling for Heavy Oil Thermal CrackingCHEMICAL ENGINEERING & TECHNOLOGY (CET), Issue 9 2007L. Yan Abstract The tighter specifications for refining products have gradually led refineries to focus on the molecular modeling of petroleum processing. In this work, a systematic methodology is presented for the molecular modeling of heavy oil thermal cracking (HOTC). This research which is based on a microscopic understanding provides a basis to achieve better design, management, optimization, and control of HOTC. The molecular information of HOTC product streams is represented in the form of a MTHS (molecular type homologous series) matrix. From consideration of the complexity of structural isomers in heavy petroleum fractions, the heavy molecules in a homologous series are grouped to reduce the dimension of the MTHS matrix. Transformation correlations are developed to capture the molecular properties of each homologous series in the MTHS matrix and to interrelate the molecular composition and bulk properties of the product streams. The HOTC process model was built on the basis of the molecular representation provided by the MTHS matrix and the transformation correlations. Two case studies are illustrated for validation of the proposed model and methodology. [source] Molecular modeling of metal complexation by a fluoroquinolone antibioticENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 11 2008Ludmilla Aristilde Abstract An understanding of the factors controlling the chemodynamics of fluoroquinolone antibiotics in different environmental matrices is a necessary prerequisite to the assessment of their potential impact on nontarget organisms in soils and receiving waters. Of particular interest are the complexes formed between fluoroquinolones and metal cations, which are believed to be important in the mechanism of sequestration of the antibiotic by minerals and natural organic matter. The structures of these complexes have not been fully resolved by conventional spectroscopy; therefore, molecular simulations may provide useful complementary insights. We present results from apparently the first molecular dynamics simulations of a widely used fluoroquinolone antibiotic, ciprofloxacin (Cipro), in aqueous complexes with five metal cations typically found in soils and surface waters: Ca2+, Mg2+, Fe2+, Na+, and K+. The interatomic potential functions employed in the simulations were validated by comparison with available structural data for solid-phase Cipro-hexahydrate and for the metal cations in aqueous solution. Although no comprehensive structural data on the aqueous complexes appear to be available, properties of the metal complexes predicted by our simulations agree with available data for solid-phase metal,Cipro complexes. Our results indicate that the ionic potential of the metal cation controls the stability of the complex formed and that the hydration number of the metal cation in aqueous solution determines its coordination number with O atoms in the metal,Cipro complex. In respect to environmental chemodynamics, our results imply that Cipro will form two configurations of bidendate chelates with metal centers on exposed surfaces of mineral oxides, water-bridged surface complexes with exchangeable cations in clay mineral interlayers, and cation-bridged complexes with functional groups in natural organic matter. [source] Deslipping of Ester Rotaxanes: A Cooperative Interplay of Hydrogen Bonding with Rotational BarriersEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 24 2003Petra Linnartz Abstract A series of rotaxanes has been synthesized which contain two ester groups in their axles. All rotaxanes bear the same tetralactam wheel. The kinetics of the de-slipping reaction of these rotaxanes were monitored in tetrachloroethane (TCE) and dimethyl sulfoxide (DMSO) resulting in the observation of a significant solvent effect. In TCE, two isomeric rotaxanes that differ merely with respect to the orientation of the ester groups show a remarkable difference in their deslipping behavior. When the ester carbonyl group is directly attached to the axle center piece, the rotaxane decomposes with a half life of ca. 10 h at 100 °C. The reverse orientation with the carbonyl group attached to the stopper blocks deslipping almost completely and a lower limit for the half life at 100 °C of 25,000 h was obtained. These results can be interpreted by inferring a cooperative action of hydrogen bonding between wheel and axle and differences in rotational barriers. Molecular modeling and AM1 calculations support this interpretation. The implications of these results for the determination of steric size and the optimization of molecular machines are discussed. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003) [source] Molecular modeling of the dimeric structure of human lipoprotein lipase and functional studies of the carboxyl-terminal domainFEBS JOURNAL, Issue 18 2002Yoko Kobayashi Lipoprotein lipase (LPL) plays a key role in lipid metabolism. Molecular modeling of dimeric LPL was carried out using insight ii based upon the crystal structures of human, porcine, and horse pancreatic lipase. The dimeric model reveals a saddle-shaped structure and the key heparin-binding residues in the amino-terminal domain located on the top of this saddle. The models of two dimeric conformations , a closed, inactive form and an open, active form , differ with respect to how surface-loop positions affect substrate access to the catalytic site. In the closed form, the surface loop covers the catalytic site, which becomes inaccessible to solvent. Large conformational changes in the open form, especially in the loop and carboxyl-terminal domain, allow substrate access to the active site. To dissect the structure,function relationships of the LPL carboxyl-terminal domain, several residues predicted by the model structure to be essential for the functions of heparin binding and substrate recognition were mutagenized. Arg405 plays an important role in heparin binding in the active dimer. Lys413/Lys414 or Lys414 regulates heparin affinity in both monomeric and dimeric forms. To evaluate the prediction that LPL forms a homodimer in a ,head-to-tail' orientation, two inactive LPL mutants , a catalytic site mutant (S132T) and a substrate-recognition mutant (W390A/W393A/W394A) , were cotransfected into COS7 cells. Lipase activity could be recovered only when heterodimerization occurred in a head-to-tail orientation. After cotransfection, 50% of the wild-type lipase activity was recovered, indicating that lipase activity is determined by the interaction between the catalytic site on one subunit and the substrate-recognition site on the other. [source] Carbonyl reductase 1 as a novel target of (,)-epigallocatechin gallate against hepatocellular carcinoma,HEPATOLOGY, Issue 2 2010Weixue Huang Human carbonyl reductase 1 (CBR1) converts the antitumor drug and anthracycline daunorubicin (DNR) into the alcohol metabolite daunorubicinol (DNROL) with significantly reduced antitumor activity and cardiotoxicity, and this limits the clinical use of DNR. Inhibition of CBR1 can thus increase the efficacy and decrease the toxicity of DNR. Here we report that (,)-epigallocatechin gallate (EGCG) from green tea is a promising inhibitor of CBR1. EGCG directly interacts with CBR1 and acts as a noncompetitive inhibitor with respect to the cofactor reduced nicotinamide adenine dinucleotide phosphate and the substrate isatin. The inhibition is dependent on the pH, and the gallate moiety of EGCG is required for activity. Molecular modeling has revealed that EGCG occupies the active site of CBR1. Furthermore, EGCG specifically enhanced the antitumor activity of DNR against hepatocellular carcinoma SMMC7721 cells expressing high levels of CBR1 and corresponding xenografts. We also demonstrated that EGCG could overcome the resistance to DNR by Hep3B cells stably expressing CBR1 but not by RNA interference of CBR1-HepG2 cells. The level of the metabolite DNROL was negatively correlated with that of EGCG in the cell extracts. Finally, EGCG decreased the cardiotoxicity of DNR in a human carcinoma xenograft model with both SMMC7721 and Hep3B cells in mice. Conclusion: These results strongly suggest that EGCG can inhibit CBR1 activity and enhance the effectiveness and decrease the cardiotoxicity of the anticancer drug DNR. These findings also indicate that a combination of EGCG and DNR might represent a novel approach for hepatocellular carcinoma therapy or chemoprevention. (HEPATOLOGY 2010;) [source] Kinetic and heat transfer modeling of rubber blends' sulfur vulcanization with N - t -butylbenzothiazole-sulfenamide and N,N -di- t -butylbenzothiazole-sulfenamideJOURNAL OF APPLIED POLYMER SCIENCE, Issue 1 2007Likozar Abstract Vulcanization kinetics and heat transfer for various blends of natural (NR) and polybutadiene (BR) rubber were studied simultaneously using a mechanistic approach when developing vulcanization model kinetics. Rubber process analyzer (RPA), dynamic scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR) methods were used for the study. The model reaction scheme was based on one of the best possible proposed individual reaction mechanisms. Molecular modeling was applied to distinguish between the reactivity of chemically similar species. The kinetics of N - t -butylbenzothiazole-sulfenamide (TBBS) and N,N -di- t -butylbenzothiazole-sulfenamide (TBSI) were treated separately using FTIR experiment data, and then incorporated in a model suitable for two-accelerator vulcanization. The proposed model quite well describes the thermal equilibration during the induction period despite a few simplifications. During cure and over-cure periods the course of vulcanization was described using a rigorous kinetic model. Physical and chemical model parameters were calculated from experimental data. Average heat transfer coefficient minimum during induction period was found to be at a weight ratio of BR and NR 1 : 1. The activation energy of significant reactions between rubber and other species was found to vary linearly with vulcanization compound composition. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 103: 293,307, 2007 [source] Theoretical study of the interaction between a high-valent manganese porphyrin oxyl-(hydroxo)-Mn(IV)-TMPyP and double-stranded DNAJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 7 2003Philippe Arnaud Abstract Cationic porphyrin derivatives such as meso-tetrakis(4- N -methylpyridinium)porphyrin, TMPyP, have been shown to interact with double-stranded DNA. The manganese derivative, Mn(III)-TMPyP, activated by an oxygen donor like potassium monopersulfate, provides an efficient DNA-cleaving system. Previous experimental work1 has shown that DNA cleavage by the Mn(III)-TMPyP/KHSO5 system was due to an oxidative attack, within the minor groove of B-DNA, at the C5, or C1, carbons of deoxyribose units. The aim of this study was to use molecular modeling to elucidate the specificity of the interactions between the transient active species oxyl-Mn(IV)-TMPyP and the DNA target. Geometric parameters, charges, and force field constants consistent with the AMBER 98 force field were calculated by DFT methods. Molecular modeling (mechanics and dynamic simulations) were performed for oxyl-(hydroxo)-Mn(IV)-TMPyP bound in the minor groove of the dodecamer d(5,-TCGTCAAACCGC)-d(5,-GCGGTTTGACGA). Geometry, interactions, and binding energy of the metalloporphyrin located at the A.T triplet region of the dodecamer were analyzed. These studies show no significant structural change of the DNA structure upon ligand binding. Mobility of the metalloporphyrin in the minor groove was restrained by the formation of a hydrogen bond between the hydroxo ligand trans to the metal-oxyl and a DNA phosphate, restricting the access of the oxyl group to the (pro-S) H atom at C5,. © 2003 Wiley Periodicals, Inc. J Comput Chem 24: 797,805, 2003 [source] Molecular modeling of responsive polymer filmsAICHE JOURNAL, Issue 8 2010Mario Tagliazucchi First page of article [source] (+)- and (-)- cis -2-Aminomethylcyclopropanecarboxylic Acids Show Opposite Pharmacology at Recombinant ,1 and ,2 GABAC ReceptorsJOURNAL OF NEUROCHEMISTRY, Issue 6 2000Rujee K. Duke Abstract: The effects of the enantiomers of (±)-CAMP and(±)-TAMP [(±)- cis - and(±)- trans -2-aminomethylcyclopropanecarboxylic acids,respectively], which are cyclopropane analogues of GABA, were tested onGABAA and GABAC receptors expressed in Xenopuslaevis oocytes using two-electrode voltage clamp methods. (+)-CAMP wasfound to be a potent and full agonist at homooligomeric GABACreceptors (KD,40 ,M andImax,100% at ,1;KD,17 ,M and Imax,100% at ,2) but a very weak antagonist at,1,2,2L GABAAreceptors. In contrast, (-)-CAMP was a very weak antagonist at both,1,2,2L GABAAreceptors and homooligomeric GABAC receptors (IC50,900 ,M at ,1 and ,400 ,M at,2). Furthermore, (+)-CAMP appears to be a superior agonist tothe widely used GABAC receptor partial agonistcis -4-aminocrotonic acid (KD,74,M and Imax,78% at ,1;KD,70 ,M and Imax,82% at ,2). (-)-TAMP was the most potent of thecyclopropane analogues on GABAC receptors (KD,9 ,M and Imax,40% at,1; KD,3 ,M andImax,50-60% at ,2), but it was also amoderately potent GABAA receptor partial agonist(KD,50-60 ,M and Imax,50% at ,1,2,2LGABAA receptors). (+)-TAMP was a less potent partial agonist atGABAC receptors (KD,60 ,M andImax,40% at ,1; KD,30 ,M and Imax,60% at,2) and a weak partial agonist at,1,2,2L GABAAreceptors (KD,500 ,M andImax,50%). None of the isomers of (±)-CAMP and(±)-TAMP displayed any interaction with GABA transport at theconcentrations tested. Molecular modeling based on the present resultsprovided new insights into the chiral preferences for either agonism orantagonism at GABAC receptors. [source] Molecular modeling of H2 purification on Na-LSX zeolite and experimental validationAICHE JOURNAL, Issue 1 2005B. Weinberger Analysis of hydrogen purification process by adsorption in the dehydrated Na-LSX zeolite is described. New measurements of hydrogen and nitrogen adsorption selectivity of this zeolite have been performed up to a pressure of 20 MPa and at temperatures of 273, 293 and 313 K, by using a gravimetric-volumetric method. Structural characterizations were realized by helium density displacement, nuclear magnetic resonance, X-ray diffraction and scanning electronic microscopy. Furthermore, Monte Carlo simulations of gas adsorption were performed in a zeolite model of Na-LSX, using pair potentials to represent the interaction between gas molecules and zeolite atoms. Comparison of simulation results and experimental data enabled testing of the validity of such a modeling of the gas-zeolite interaction. © 2004 American Institute of Chemical Engineers AIChE J, 51:142,148, 2005 [source] Effect of hindered piperidine light stabilizer molecular structure and UV absorber addition on the oxidation of HDPE.JOURNAL OF VINYL & ADDITIVE TECHNOLOGY, Issue 4 2004Part 2: Mechanistic aspects, electron spin resonance spectroscopy study, molecular modeling The first in this series of papers explored the effect of the structural characteristics of 2,2,6,6-tetramethylpiperidine-based hindered amine light stabilizers (HALS) on the thermal and photostabilization of high-density polyethylene. In the second part, the energies (stabilities) of the nitroxyl radicals and various intermediate species have been predicted using AccuModel® and related to stabilization performance and electron spin resonance (ESR) spectral data. Nitroxyl radicals with low predicted stability generally afforded improved thermal and photostabilization. ESR spectra were used to obtain values of nitroxyl radical concentration ([>NO·]) and g -factor as a function of pre-aging time for combinations of pre-aged HDPE and >NH HALS. Demethylation reactions of > N-methyl HALS resulted in uselessly weak ESR spectra. The HALS that afforded poor thermal oxidative stabilization gave rise to pronounced minima in [>NO·] that coincided with a maximum in hydroperoxide concentration. The g -factor values indicated that a predominant nitroxyl canonical form generally promoted superior thermal oxidative stabilization, whereas a predominance of the dipolar N·+O, form promoted superior photo-oxidative stabilization. These trends may be related to greater radical-scavenging and peroxide-trapping effects, respectively. Molecular modeling and ESR spectra can therefore provide valuable insight into the effectiveness of HALS and stabilization mechanisms. J. Vinyl Addit. Technol. 10:159,167, 2004. © 2004 Society of Plastics Engineers. [source] Structure determination and conformation analysis of symmetrical dimersMAGNETIC RESONANCE IN CHEMISTRY, Issue 3 2005Alexei V. Buevich Abstract Conformational and stereochemical analysis of six new symmetrical dimers was performed using proton,proton vicinal coupling measured from 1H NMR and 13C satellites of 1H NMR signals, natural abundance 13C-edited nuclear overhauser effect (NOE) experiments, comprehensive NOE analysis and molecular modeling. The 13C satellite analysis and 13C-edited NOE experiments were carried out to extract spectral information between equivalent protons. Molecular modeling was applied for estimations of three-dimensional parameters of the studied dimers, which were subsequently used to generate a set of theoretical NOE for each possible conformation. The J -coupling, 13C-edited NOE and quantitative NOE analyses showed the predominance of gauche conformation for three dimers, whereas a mixture of gauche and anti conformations (45:55) for three other dimers was established by quantitative NOE analysis. X-ray crystallographic study confirmed the stereochemistry of one of the dimers and revealed a discrepancy in conformation stability between liquid and solid states. Copyright © 2004 John Wiley & Sons, Ltd. [source] Allergen IgE-isotype-specific suppression by maternally derived monoclonal anti-IgG-idiotypeALLERGY, Issue 1 2010R. I. Tanasa Abstract Background:, The dramatic increase of IgE-mediated allergic diseases in western countries demonstrates the urgent need for new therapeutic or prophylactic approaches. In mice, a prophylactic long-lasting allergen-specific suppression of IgE responsiveness is induced by maternal IgG antibodies to allergens like ovalbumin, phospholipase A2 (bvPLA2) or ovomucoid. As neonatal application or maternally derived pathogen-reactive antibodies (idiotypes) as well as corresponding anti-idiotypes can induce anti-microbial protection, we probed the transgenerational IgE-suppressive mechanism with a syngeneic monoclonal anti-idiotypic antibody. Methods:, The monoclonal bee-venom-phospholipase A2 (bvPLA2)-reactive IgG antibody MS613 (idiotype) or the corresponding syngeneic anti-idiotype II/2-19 were injected during the first 2 days postpartum to the dams. Immunization of offspring with minute doses of IgE-inducing bvPLA2 was started at an adult age of 3½ months. Results:, The postnatal transfer of the anti-bvPLA2 idiotype MS613 or the corresponding anti-idiotype II/2-19 induced long-lasting allergen-specific IgE suppression in a dose-dependent manner, while the IgG response to the allergen developed normally. Quantitatively, the anti-idiotype was more effective than idiotype. Molecular modeling of the idiotype-anti-idiotype complex and its comparison with the bvPLA2 structure revealed that the anti-idiotype does not mimic bvPLA2 epitopes and thus can not be regarded as an internal image antibody and, consequently, does not function as a surrogate antigen. Conclusions:, Idiotypic network reactivity is at least one major factor for induction of transgenerational IgE suppression by maternal IgG antibodies. If applicable to humans, these data suggest the possibility of a prophylactic and possibly therapeutic treatment of IgE-mediated allergic diseases with anti-idiotypic antibodies. [source] Stoichiometry of lipid interactions with transmembrane proteins,Deduced from the 3D structuresPROTEIN SCIENCE, Issue 5 2006Tibor Páli Abstract The stoichiometry of the first shell of lipids interacting with a transmembrane protein is defined operationally by the population of spin-labeled lipid chains whose motion is restricted directly by the protein. Interaction stoichiometries have been determined experimentally for a wide range of ,-helical integral membrane proteins by using spin-label ESR spectroscopy. Here, we determine the spatially defined number of first-shell lipids at the hydrophobic perimeter of integral membrane proteins whose 3D structure has been determined by X-ray crystallography and lipid,protein interactions characterized by spin-labeling. Molecular modeling is used to build a single shell of lipids surrounding transmembrane structures derived from the PDB. Constrained energy optimization of the protein,lipid assemblies is performed by molecular mechanics. For relatively small proteins (up to 7,12 transmembrane helices), the geometrical first shell corresponds to that defined experimentally by perturbation of the lipid-chain dynamics. For larger, multi-subunit ,-helical proteins, the lipids perturbed directly by the protein may either exceed or be less in number than those that can be accommodated at the intramembranous perimeter. In these latter cases, the motionally restricted spin-labeled lipids can be augmented by intercalation, or can correspond to a specific subpopulation at the protein interface, respectively. For monomeric ,-barrel proteins, the geometrical lipid stoichiometry corresponds to that determined from lipid mobility for a 22-stranded barrel, but fewer lipids are motionally restricted than can be accommodated around an eight-stranded barrel. Deviations from the geometrical first shell, in the ,-barrel case, are for the smaller protein with a highly curved barrel. [source] Molecular modeling of estrogen receptor using molecular operating environmentBIOCHEMISTRY AND MOLECULAR BIOLOGY EDUCATION, Issue 4 2007Urmi Roy Abstract Molecular modeling is pervasive in the pharmaceutical industry that employs many of our students from Biology, Chemistry and the interdisciplinary majors. To expose our students to this important aspect of their education we have incorporated a set of tutorials in our Biochemistry class. The present article describes one of our tutorials where undergraduates use modeling experiments to explore the structure of an estrogen receptor. We have employed the Molecular Operating Environment, a powerful molecular visualization software, which can be implemented on a variety of operating platforms. This tutorial reinforces the concepts of ligand binding, hydrophobicity, hydrogen bonding, and the properties of side chains and secondary structure taught in a general biochemistry class utilizing a protein that has importance in human biology. [source] Learning from Directed Evolution: Theoretical Investigations into Cooperative Mutations in Lipase EnantioselectivityCHEMBIOCHEM, Issue 2 2004Marco Bocola Dr. Abstract Molecular modeling with classical force-fields has been used to study the reactant complex and the tetrahedral intermediate in lipase-catalyzed ester hydrolysis in 20 enzyme/substrate combinations. The R and S enantiomers of,-methyldecanoic acid ester served as substrates for the wild-type lipase from Pseudomonas aeruginosa and nine selected mutants. After suitable preparation of initial structures from an available wild-type crystal structure, each system was subjected to 1 ns CHARMM force-field molecular dynamics simulations. The resulting geometric and energetic changes allow interpretation of some experimentally observed effects of mutations, particularly with regard to the "hot spots" at residues 155 and 162. The replacement S155F enhances S enantiopreference through a steric relay involving Leu162. The double mutation S53P + L162G improves S enantioselectivity by creating a new binding pocket for the S enantiomer with an additional stabilizing hydrogen bond to His83. The simulations provide insight into remote and cooperative effects of mutations. [source] One-Armed Artificial Receptors for the Binding of Polar Tetrapeptides in Water: Probing the Substrate Selectivity of a Combinatorial Receptor LibraryCHEMISTRY - A EUROPEAN JOURNAL, Issue 5 2006Carsten Schmuck Prof. Dr. Abstract We have recently developed a new class of one-armed artificial receptors 1 for the binding of the polar tetrapeptide N -Ac- D -Glu- L -Lys- D -Ala- D -Ala-OH (EKAA) 2 in water using a combined combinatorial and statistical approach. We have now further probed the substrate selectivity of this receptor library 1 by screening a second tetrapeptide substrate (3) with the inverse sequence N -Ac- D -Ala- D -Ala- L -Lys- D -Glu-OH (AAKE). This "inverse" substrate is also efficiently bound by our receptors, with Kass ,6000,m,1 for the best receptors, as determined both by a quantitative on-bead binding assay and by UV and fluorescence titration studies in free solution. Hence, the inverse tetrapeptide 3 is in general bound two to three times less efficiently than the "normal" peptide 2 (Kass ,17,000,m,1), even though the complexation mainly involves long-range electrostatic interactions and both the receptor and substrate are rather flexible. Molecular modeling and ab initio calculations have been used to rationalize the observed substrate selectivity and to analyze the various binding interactions within the complex. [source] | ||||||||||||||||||||||||||||||||||||||||||||||