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Molecular Models (molecular + models)
Selected AbstractsModeling dioxygen binding to the non-heme iron-containing enzymesINTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, Issue 10 2006A. V. Nemukhin Abstract The structures and properties of the complexes formed upon binding the oxygen molecule to the iron sites in non-heme 2-oxoglutarate-dependent enzymes are characterized by QM(CASSCF)/MM and density functional theory (DFT) calculations. Molecular models for the calculations are constructed following the crystal structure of hypoxia-inducible factor asparaginyl hydroxylase (FIH-1). DFT calculations for the 37-atomic cluster have been carried out at the B3LYP(LANL2DZdp) level. The flexible effective fragment potential method is used as a combined quantum mechanical,molecular mechanical (QM/MM) technique to characterize the fragment of the enzymatic system, including 1,758 atoms in the MM part and 27 atoms in the QM part. In these calculations, the CASSCF(LANL2DZdp) approach is applied in the QM subsystem, and AMBER force field parameters are used in the MM subsystem. With both approaches, equilibrium geometry configurations have been located for different spin states of the system. In DFT calculations, the order of the states is as follows: septet, triplet (+7.7 kcal/mol), quintet (+10.7 kcal/mol). Geometry configurations correspond to the end-on structures with no evidences of electron transfer from Fe(II) to molecular oxygen. In contrast, QM(CASSCF)/MM calculations predict the quintet state as the lowest one, while the septet structure has slightly (<2 kcal/mol) higher energy, and the triplet state is considerably more energetic. In QM/MM calculations, in both quintet and septet states, the electronic configurations show considerable electron charge transfer from iron to oxygen, and the oxidation state of iron in the metal binding site can be characterized as Fe(III). © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2006 [source] An examination of binding motifs associated with inter-particle interactions between facetted nano-crystals of acetylsalicylic acid and ascorbic acid through the application of molecular grid-based search methods,JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 12 2009R.B. Hammond Abstract Grid-based intermolecular search methods using atom,atom force fields are used to assess the structural nature of potential crystal,crystal interfacial binding associated with the examination of representative pharmaceutical formulation components, viz acetylsalicylic acid (aspirin) and ascorbic acid (vitamin C). Molecular models of nano-sized molecular clusters for these two compounds, shaped in accordance with an attachment energy model of the respective particle morphologies, are constructed and used together with a grid-based search method to model the likely inter-particle interactions. The most-stable, mutual alignments of the respective nano-clusters based on their interaction energies are identified in the expectation that these are indicative of the most likely inter-particle binding configurations. The stable inter-particle binding configurations identified reveal that the number of interfacial hydrogen bonds formed between the binding particles is, potentially, an important factor in terms of the stability of inter-particle cohesion. All preferred inter-particle alignments are found to involve either the (1,0,0) or the (1,1,0) face of aspirin crystals interacting with a number of the growth forms of ascorbic acid. Four main types of interfacial hydrogen bonds are found to be associated with inter-particle binding and involve acceptor,donor interactions between hydroxyl, carbonyl, ester and lactone acceptor groups and hydroxyl donor groups. This hydrogen bonding network is found to be consistent with the surface chemistry of the interacting habit faces with, in general, the number of hydrogen bonds increasing for the more stable alignments. The likely usefulness of this approach for predicting solid-state formulation properties is reviewed. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4589,4602, 2009 [source] Molecular models of the procoagulant Factor VIIIa,Factor IXa complexJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 9 2005L. AUTIN Summary.,Background:,Formation of the intrinsic tenase complex is an essential event in the procoagulant reactions that lead to clot formation. The tenase complex is formed when the activated serine protease, Factor IXa (FIXa), and its cofactor Factor VIIIa (FVIIIa) assemble on a phospholipid surface to proteolytically convert the zymogen Factor X (FX) into its active form FXa. The physiological relevance of the tenase complex is evident in hemophilia A or B patients who present with bleeding disorders. Objectives:,The purpose of this study was to establish three-dimensional (3D) models of the FVIIIa,FIXa complex. Methods:,First, we built two new theoretical models of FVIIIa via homology modeling, inter-domain docking and loop simulation algorithms as well as a model for FIXa. This was followed by pseudo-Brownian protein,protein docking in internal coordinates with the ICM (Internal Coordinates Mechanics) program between the two FVIIIa and the FIXa structures. Results:,Ten representative models of this complex are presented based on agreements with known experimental data and according to structural criteria. Conclusions:,These novel 3D models will help guide future site directed mutagenesis aimed at improving the functionality of FVIIIa and/or FIXa and will contribute to a better understanding of the role of this macromolecular complex in the blood coagulation cascade. [source] Knowledge-Based Tailoring of Gelatin-Based Materials by Functionalization with Tyrosine-Derived GroupsMACROMOLECULAR RAPID COMMUNICATIONS, Issue 17 2010Axel Thomas Neffe Abstract Molecular models of gelatin-based materials formed the basis for the knowledge-based design of a physically cross-linked polymer system. The computational models with 25,wt.-% water content were validated by comparison of the calculated structural properties with experimental data and were then used as predictive tools to study chain organization, cross-link formation, and estimation of mechanical properties. The introduced tyrosine-derived side groups, desaminotyrosine (DAT) and desaminotyrosyl tyrosine (DATT), led to the reduction of the residual helical conformation and to the formation of physical net-points by ,,, interactions and hydrogen bonds. At 25,wt.-% water content, the simulated and experimentally determined mechanical properties were in the same order of magnitude. The degree of swelling in water decreased with increasing the number of inserted aromatic functions, while Young's modulus, elongation at break, and maximum tensile strength increased. [source] Cover Picture: Plasma Process.PLASMA PROCESSES AND POLYMERS, Issue 8 2005Polym. Cover: The Figure shows the X-ray photoelectron spectra of the nitrogen 1s core levels and the near edge X-ray fine structure nitrogen K edge of plasma polymers and plasma co-polymers prepared from allylamine and mixtures of acrylic acid and allylamine. Molecular models of allylamine, acrylic acid and allylammonium acrylate salt are shown to illustrate the chemistry. This is shown on a background of a micrograph of melanocytes cultured on a plasma polymer coating. The micrograph has been artificially colourised. Further details can be found in the Full Paper by A. J. Beck,* J. D. Whittle, N. A. Bullett, P. Eves, S. Mac Neil, S. L. McArthur, and A. G. Shard on page 641. [source] An actin-stabilizing peptide conjugate deduced from the major outer sheath protein of the bacterium Treponema denticolaCYTOSKELETON, Issue 9 2007Mohsen Amin Abstract A synthetic peptide conjugated to bovine serum albumin, P34BSA, based on a 10-mer in the deduced amino acid sequence of the major outer sheath protein of Treponema denticola, was found to stabilize actin filaments of fibroblasts. Pretreatment of cells with P34BSA inhibited the actin disruption induced by cytochalasin D and latrunculin B. P34BSA was taken up by the cells and localized among actin filaments. P34BSA bound actin from fibroblast lysates, and cell exposure to P34BSA led to the activation of RhoA, a key regulator of actin filament assembly in fibroblasts. Exposure of fibroblasts to P34BSA retarded their migration on a collagen substratum. P34BSA also inhibited chemotaxis of murine neutrophils. Our findings with a novel peptide conjugate imply that bacterial proteins known to perturb the cytoskeleton represent a rich source of molecular models upon which to design synthetic reagents for modulating actin-dependent cellular functions. Cell Motil. Cytoskeleton 2007. © 2007 Wiley-Liss, Inc. [source] Interpretation of biological activity data of bacterial endotoxins by simple molecular models of mechanism of actionFEBS JOURNAL, Issue 3 2000Vladimir Frecer Lipid A moiety has been identified as the bioactive component of bacterial endotoxins (lipopolysaccharides). However, the molecular mechanism of biological activity of lipid A is still not fully understood. This paper contributes to understanding of the molecular mechanism of action of bacterial endotoxins by comparing molecular modelling results for two possible mechanisms with the underlying experimental data. Mechanisms of action involving specific binding of lipid A to a protein receptor as well as nonspecific intercalation into phospholipid membrane of a host cell were modelled and analysed. As the cellular receptor for endotoxin has not been identified, a model of a peptidic pseudoreceptor was proposed, based on molecular structure, symmetry of the lipid A moiety and the observed character of endotoxin-binding sites in proteins. We have studied the monomeric form of lipid A from Escherichia coli and its seven synthetic analogues with varying numbers of phosphate groups and correlated them with known biological activities determined by the Limulus assay. Gibbs free energies associated with the interaction of lipid A with the pseudoreceptor model and intercalation into phospholipid membrane calculated by molecular mechanics and molecular dynamics methods were used to compare the two possible mechanisms of action. The results suggest that specific binding of lipid A analogues to the peptidic pseudoreceptor carrying an amphipathic cationic binding pattern BHPHB (B, basic; H, hydrophobic; P, polar residue, respectively) is energetically more favourable than intercalation into the phospholipid membrane. In addition, binding affinities of lipid A analogues to the best minimum binding sequence KFSFK of the pseudoreceptor correlated with the experimental Limulus activity parameter. This correlation enabled us to rationalize the observed relationship between the number and position of the phosphate groups in the lipid A moiety and its biological activity in terms of specific ligand,receptor interactions. If lipid A,receptor interaction involves formation of phosphate-ammonium ion-pair(s) with cationic amino-acid residues, the specific mechanism of action was fully consistent with the underlying experimental data. As a consequence, recognition of lipid A variants by an amphipathic binding sequence BHPHB of a host-cell protein receptor might represent the initial and/or rate-determining molecular event of the mechanism of action of lipid A (or endotoxin). The insight into the molecular mechanism of action and the structure of the lipid A-binding pattern have potential implications for rational drug design strategies of endotoxin-neutralizing agents or binding factors. [source] Functional roles of the factor VIII B domainHAEMOPHILIA, Issue 6 2009S. W. PIPE Summary., Unravelling the structure, function and molecular interactions of factor VIII (FVIII) throughout its life cycle from biosynthesis to clearance has advanced our understanding of the molecular mechanisms of haemophilia and the development of effective treatment strategies including recombinant replacement therapy. These insights are now influencing bioengineering strategies toward novel therapeutics. Whereas available molecular models and crystal structures have helped elucidate the structure and function of the A and C domains of FVIII, these models have not included detailed structural information of the B domain. Therefore, insights into the role of the FVIII B domain have come primarily from expression studies in heterologous systems, biochemical studies on bioengineered FVIII variants and clinical studies with B domain-deleted FVIII. This manuscript reviews the available data on the potential functional roles of the FVIII B domain. A detailed literature search was performed, and the data extracted were qualitatively summarized. Intriguing emerging evidence suggests that the FVIII B domain is involved in intracellular interactions that regulate quality control and secretion, as well as potential regulatory roles within plasma during activation, platelet binding, inactivation and clearance. [source] Asymmetric Reduction of Activated Alkenes by Pentaerythritol Tetranitrate Reductase: Specificity and Control of Stereochemical Outcome by Reaction OptimisationADVANCED SYNTHESIS & CATALYSIS (PREVIOUSLY: JOURNAL FUER PRAKTISCHE CHEMIE), Issue 17 2009Anna Fryszkowska Abstract We show that pentaerythritol tetranitrate reductase (PETNR), a member of the ,ene' reductase old yellow enzyme family, catalyses the asymmetric reduction of a variety of industrially relevant activated ,,,-unsaturated alkenes including enones, enals, maleimides and nitroalkenes. We have rationalised the broad substrate specificity and stereochemical outcome of these reductions by reference to molecular models of enzyme-substrate complexes based on the crystal complex of the PETNR with 2-cyclohexenone 4a. The optical purity of products is variable (49,99% ee), depending on the substrate type and nature of substituents. Generally, high enantioselectivity was observed for reaction products with stereogenic centres at C, (>99% ee). However, for the substrates existing in two isomeric forms (e.g., citral 11a or nitroalkenes 18,19a), an enantiodivergent course of the reduction of E/Z -forms may lead to lower enantiopurities of the products. We also demonstrate that the poor optical purity obtained for products with stereogenic centres at C, is due to non-enzymatic racemisation. In reactions with ketoisophorone 3a we show that product racemisation is prevented through reaction optimisation, specifically by shortening reaction time and through control of solution pH. We suggest this as a general strategy for improved recovery of optically pure products with other biocatalytic conversions where there is potential for product racemisation. [source] Large-scale molecular dynamics simulations of HLA-A*0201 complexed with a tumor-specific antigenic peptide: Can the ,3 and ,2m domains be neglected?JOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 15 2004Shunzhou Wan Abstract Large-scale massively parallel molecular dynamics (MD) simulations of the human class I major histocompatibility complex (MHC) protein HLA-A*0201 bound to a decameric tumor-specific antigenic peptide GVYDGREHTV were performed using a scalable MD code on high-performance computing platforms. Such computational capabilities put us in reach of simulations of various scales and complexities. The supercomputing resources available for this study allow us to compare directly differences in the behavior of very large molecular models; in this case, the entire extracellular portion of the peptide,MHC complex vs. the isolated peptide binding domain. Comparison of the results from the partial and the whole system simulations indicates that the peptide is less tightly bound in the partial system than in the whole system. From a detailed study of conformations, solvent-accessible surface area, the nature of the water network structure, and the binding energies, we conclude that, when considering the conformation of the ,1,,2 domain, the ,3 and ,2m domains cannot be neglected. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 1803,1813, 2004 [source] Elucidating the higher-order structure of biopolymers by structural probing and mass spectrometry: MS3DJOURNAL OF MASS SPECTROMETRY (INCORP BIOLOGICAL MASS SPECTROMETRY), Issue 8 2010Daniele Fabris Abstract Chemical probing represents a very versatile alternative for studying the structure and dynamics of substrates that are intractable by established high-resolution techniques. The implementation of MS-based strategies for the characterization of probing products has not only extended the range of applicability to virtually all types of biopolymers but has also paved the way for the introduction of new reagents that would not have been viable with traditional analytical platforms. As the availability of probing data is steadily increasing on the wings of the development of dedicated interpretation aids, powerful computational approaches have been explored to enable the effective utilization of such information to generate valid molecular models. This combination of factors has contributed to making the possibility of obtaining actual 3D structures by MS-based technologies (MS3D) a reality. Although approaches for achieving structure determination of unknown targets or assessing the dynamics of known structures may share similar reagents and development trajectories, they clearly involve distinctive experimental strategies, analytical concerns and interpretation paradigms. This Perspective offers a commentary on methods aimed at obtaining distance constraints for the modeling of full-fledged structures while highlighting common elements, salient distinctions and complementary capabilities exhibited by methods used in dynamics studies. We discuss critical factors to be addressed for completing effective structural determinations and expose possible pitfalls of chemical methods. We survey programs developed for facilitating the interpretation of experimental data and discuss possible computational strategies for translating sparse spatial constraints into all-atom models. Examples are provided to illustrate how the concerted application of very diverse probing techniques can lead to the solution of actual biological systems. Copyright © 2010 John Wiley & Sons, Ltd. [source] Structural motifs in the maturation process of peptide hormones.JOURNAL OF PEPTIDE SCIENCE, Issue 2 2002The somatostatin precursor. Abstract Synthetic peptides reproducing both the native domain around the dibasic cleavage site of pro-somatostatin, and mutated sequences thereof, previously assayed in site-directed mutagenesis experiments, have been studied by CD in different solvent systems, such as water, TFE/H2O, MeCN/H2O and aqueous SDS, in order to ascertain the ability of each solvent to stabilize secondary structural motifs. A combination of deconvolution methods and empirical calculations, that allow subtraction of the contributions due to unordered structures from the spectra, suggests that mainly two distinct families of ordered conformers containing ,-helix and/or structurally different ,-turns are present in solution, the relative stability of the different conformers depending on the nature of the solvent. The presence of ,-turns is in line with a previous NMR study in DMSO and DMSO/H2O. Comparison of the CD spectra in aqueous SDS of peptides undergoing processing with a sequence not processed in vivo shows that only the latter possesses a stable and detectable ,-helix population. This observation suggests that the structuration involving ,-turns but no ,-helix, which was observed by CD both in SDS and organic solvent/H2O mixtures at high water contents, might be of biological significance. The similarity of this structuration to molecular models obtained from NMR data in DMSO and DMSO/H2O is discussed. Copyright © 2002 European Peptide Society and John Wiley & Sons, Ltd. [source] Brassinosteroids and plant function: some clues, more puzzlesPLANT CELL & ENVIRONMENT, Issue 3 2006L. L. HAUBRICK ABSTRACT The role of brassinosteroids (BRs) in plant function has been intensively studied in the last few years. Mutant analysis has demonstrated that the ability to synthesize, perceive and respond to BRs is essential to normal plant growth and development. Several key elements of BR response have been identified using both genetic and biochemical approaches, and molecular models that parallel Wingless (Wnt), transforming growth factor , (TGF,) and receptor tyrosine kinase (RTK) signalling in animals have been proposed. Many studies have demonstrated the role of BRs, alone and in interaction with other plant hormones, in processes such as cell elongation and seed germination. In contrast, little is known about how the sensing of BRs is connected to specific physiological responses such as stress resistance. There remain many open questions about how these connections are made. [source] Animal models of fetal renal diseasePRENATAL DIAGNOSIS, Issue 11 2001Craig A. Peters Abstract Fetal models of urinary tract disease have been used for many years and have provided unique and important insights into the pathophysiology of these conditions. This review will summarize the principal model systems used and the current directions of investigation. These models (including rabbit, opossum, sheep and recently swine) have demonstrated that in utero obstruction of the urinary tract alters renal growth, differentiation and produces stereotypical patterns of tissue response, particularly fibrosis. New molecular understanding of these processes has identified specific mechanisms that may be key elements in the development of renal dysfunction due to obstruction. These factors include the renin,angiotensin system (RAS) and its interaction with TGF-, in altering growth regulation and tissue fibrosis. These factors offer the prospect of clinical utility as markers of disease progression as well as pharmacologic therapy. Gene knockout systems have opened a new horizon of molecular models of congenital obstructive uropathy with insights into the role of the RAS in particular. It remains to be defined how closely these knockouts represent the human conditions they resemble. Continued application of fetal models of urinary obstruction, integrating large animal and knockout systems offers promise for improved diagnosis and treatment in these challenging conditions. Copyright © 2001 John Wiley & Sons, Ltd. [source] Specific reactions of S -nitrosothiols with cysteine hydrolases: A comparative study between dimethylargininase-1 and CTP synthetasePROTEIN SCIENCE, Issue 8 2007Oliver Braun Abstract S-Transnitrosation is an important bioregulatory process whereby NO+ equivalents are transferred between S -nitrosothiols and Cys of target proteins. This reaction proceeds through a common intermediate R,S,N(O,),S,R, and it has been proposed that products different from S -nitrosothiols may be formed in protein cavities. Recently, we have reported on the formation of such a product, an N -thiosulfoximide, at the active site of the Cys hydrolase dimethylargininase-1 (DDAH-1) upon reaction with S -nitroso- l -homocysteine (HcyNO). Here we have addressed the question of whether this novel product can also be formed with the endogenously occurring S -nitrosothiols S -nitroso- l -cysteine (CysNO) and S -nitrosoglutathione (GSNO). Further, to explore the reason responsible for the unique formation of an N -thiosulfoximide in DDAH-1 we have expanded these studies to cytidine triphosphate synthetase (CTPS), which shows a similar active site architecture. ESI-MS and activity measurements showed that the bulky GSNO does not react with both enzymes. In contrast, S-nitrosylation of the active site Cys occurred in DDAH-1 with CysNO and in CTPS with CysNO and HcyNO. Although kinetic analysis indicated that these compounds act as specific irreversible inhibitors, no N -thiosulfoximide was formed. The reasons likely responsible for the absence of the N -thiosulfoximide formation are discussed using molecular models of DDAH-1 and CTPS. In tissue extracts DDAH was inhibited only by HcyNO, with an IC50 value similar to that of the isolated protein. Biological implications of these studies for the function of both enzymes are discussed. [source] Polarizable atomic multipole X-ray refinement: application to peptide crystalsACTA CRYSTALLOGRAPHICA SECTION D, Issue 9 2009Michael J. Schnieders Recent advances in computational chemistry have produced force fields based on a polarizable atomic multipole description of biomolecular electrostatics. In this work, the Atomic Multipole Optimized Energetics for Biomolecular Applications (AMOEBA) force field is applied to restrained refinement of molecular models against X-ray diffraction data from peptide crystals. A new formalism is also developed to compute anisotropic and aspherical structure factors using fast Fourier transformation (FFT) of Cartesian Gaussian multipoles. Relative to direct summation, the FFT approach can give a speedup of more than an order of magnitude for aspherical refinement of ultrahigh-resolution data sets. Use of a sublattice formalism makes the method highly parallelizable. Application of the Cartesian Gaussian multipole scattering model to a series of four peptide crystals using multipole coefficients from the AMOEBA force field demonstrates that AMOEBA systematically underestimates electron density at bond centers. For the trigonal and tetrahedral bonding geometries common in organic chemistry, an atomic multipole expansion through hexadecapole order is required to explain bond electron density. Alternatively, the addition of interatomic scattering (IAS) sites to the AMOEBA-based density captured bonding effects with fewer parameters. For a series of four peptide crystals, the AMOEBA,IAS model lowered Rfree by 20,40% relative to the original spherically symmetric scattering model. [source] A novel spectroscopic probe for molecular chiralityCHIRALITY, Issue 3 2006Na Ji Abstract Recent advances in developing sum frequency generation (SFG) as a novel spectroscopic probe for molecular chirality are reviewed. The basic principle underlying the technique is briefly described, in comparison with circular dichroism (CD). The significantly better sensitivity of the technique than CD is pointed out, and the reason is discussed. Bi-naphthol (BN) and amino acids are used as representatives for two different types of chiral molecules; the measured chirality in their electronic transitions can be understood by two different molecular models, respectively, that are extensions of models developed earlier for CD. Optically active or chiral SFG from vibrational transitions are weaker, but with the help of electronic-vibrational double resonance, the vibrational spectrum of a monolayer of BN has been obtained. Generally, optically active SFG is sufficiently sensitive to be employed to probe in-situ chirality of chiral monolayers and thin films. © 2006 Wiley-Liss, Inc. Chirality [source] | |||||||||||||||||||