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Ligand Complexes (ligand + complex)
Kinds of Ligand Complexes Selected AbstractsStructural and Theoretical Insights into Metal,Scorpionate Ligand ComplexesEUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 10 2007Matthias Schwalbe Abstract The syntheses of the complexes [M(TmMe)(CO)2(NO)] (M = Mo, W) by reaction of NOBF4 with [M(TmMe)(CO)3], are reported and their spectroscopic characterisation and crystal structures are described. The analogous Cr complex could not be prepared by this methodology. The complexes adopt the expected pseudo-octahedral geometry. Complexes [M(L)(CO)2(NO)] (M = Cr, Mo, W; L = Cp, Tp and TmMe) together with the hypothetical [Mo(CO)2(NO)]+ cation were subjected to DFT calculations. Geometry-optimised structures closely parallel the crystallographic determinations and indicate that the complex [Cr(TmMe)(CO)2(NO)] is not inherently unstable. The DFT calculations allow the assignment of the C,O and N,O stretches in the IR spectrum and give insight into both the M,NO bonding and the metal to tripodal ligand bonding. The electron-donor strengths are confirmed to lie in the order TmMe > Tp > Cp. A side reaction of the B,H moiety of the TmMe anion with NO+ results in the isolation of the dimethylformamide adduct of (trismethimazolyl)borane, providing further evidence that the reaction pathways of the TmR ligands are more varied and less passive than in the chemistry of the nitrogen-based scorpionates.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007) [source] Electronic Interactions in Ferrocene- and Ruthenocene-Functionalized Tetraazamacrcocyclic Ligand Complexes of FeII/III, CoII, NiII, CuII and ZnIIEUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 2 2005Peter Comba Abstract The syntheses of ferrocene- and ruthenocene-functionalized tetraazamacrocyclic ligands and their corresponding transition metal complexes are described. Reaction of N,N, -bis(2-aminoethyl)-1,3-propanediamine (2,3,2-tet) with 1,1,-diformylferrocene and 1,1,-diformylruthenocene produces the ligands fcmac and rcmac in 81,85% yield. Examination of their CuII, NiII, CoII, ZnII and FeII/III complexes by IR, UV/Vis, EPR and Mössbauer spectroscopy as well as by electrochemical studies suggests electronic communication between the two metal centers of each complex. The molecular structure of [CuII(fcmac)(FBF3)]BF4, determined by X-ray structure analysis, is reported and shows that the distance between the two metals is 4.54 Å. Stability constants, determined by potentiometric titration, indicate that the copper(II) complexes are of similar stability as those with unfunctionalized tetraazamacrocyclic ligands (e.g. cyclam = 1,4,8,11-tetraazacyclotetradecane); stability constants of cobalt(II) complexes are about 2 log units smaller, those of nickel(II) and zinc(II) complexes are reduced by more than 10 log units. This selectivity is discussed on the basis of the structural studies. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005) [source] Determination of Ytterbium Traces by Cathodic Stripping VoltammetryELECTROANALYSIS, Issue 1 2003Marina Mlakar Abstract The method of ytterbium(III) trace concentration in the presence of 2-thenoyltrifluoroacetone (TTA) and polyethyleneglycol (PEG) in ammonium chloride is described. The adsorption was performed at the HMDE at ,1.0,V using linear scan voltammetry and square-wave voltammetry. The relationship between properties of the SW response of the mixed ligand complex and parameters of a charge transfer were analyzed using theoretical data of SW redox processes. [source] Mutations in the Insulin-Like Factor 3 Receptor Are Associated With Osteoporosis,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 5 2008Alberto Ferlin Abstract Introduction: Insulin-like factor 3 (INSL3) is produced primarily by testicular Leydig cells. It acts by binding to its specific G protein,coupled receptor RXFP2 (relaxin family peptide 2) and is involved in testicular descent during fetal development. The physiological role of INSL3 in adults is not known, although substantial INSL3 circulating levels are present. The aim of this study was to verify whether reduced INSL3 activity could cause or contribute to some signs of hypogonadism, such as reduced BMD, currently attributed to testosterone deficiency. Materials and Methods: Extensive clinical, biochemical, and hormonal study, including bone densitometry by DXA, was performed on 25 young men (age, 27,41 yr) with the well-characterized T222P mutation in the RXFP2 gene. Expression analysis of INSL3 and RXFP2 on human bone biopsy and human and mouse osteoblast cell cultures was performed by RT-PCR, quantitative RT-PCR, and immunohistochemistry. Real-time cAMP imaging analysis and proliferation assay under the stimulus of INSL3 was performed on these cells. Lumbar spine and femoral bone of Rxfp2- deficient mice were studied by static and dynamic histomorphometry and ,CT, respectively. Results: Sixteen of 25 (64%) young men with RXFP2 mutations had significantly reduced BMD. No other apparent cause of osteoporosis was evident in these subjects, whose testosterone levels and gonadal function were normal. Expression analyses showed the presence of RXFP2 in human and mouse osteoblasts. Stimulation of these cells with INSL3 produced a dose- and time-dependent increase in cAMP and cell proliferation, confirming the functionality of the RXFP2/INSL3 receptor,ligand complex. Consistent with the human phenotype, bone histomorphometric and ,CT analyses of Rxfp2,/, mice showed decreased bone mass, mineralizing surface, bone formation, and osteoclast surface compared with wildtype littermates. Conclusions: This study suggests for the first time a role for INSL3/RXFP2 signaling in bone metabolism and links RXFP2 gene mutations with human osteoporosis. [source] Synthesis and biodistribution in mice of 99mTcN,DBODC,DMSEtJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 3 2009Shuye Yang Abstract Nitrido technetium(V)-mixed ligand complex of 99mTcN,DBODC,DMSEt [DMSEt: Monoethyl ester of (meso) 2,3-dimercaptosuccinic acid, DBODC: bis(2-ethoxyethyl)carbamodithioate] has been prepared in a two-step procedure by first reaction of 99mTcO with succinic dihydrazede in the presence of stannous chloride as a reducing agent and propylenediamine tetraacetic acid as a complexant, followed by the addition of DMSEt and DBODC. The complex was stable over 6,h at room temperature. The partition coefficient indicated that it was a hydrophilic complex. Biodistribution in mice demonstrated that the complex accumulated mainly in liver, lungs and kidneys. Copyright © 2009 John Wiley & Sons, Ltd. [source] Interaction of ACTH synthetic fragments with rat adrenal cortex membranesJOURNAL OF PEPTIDE SCIENCE, Issue 8 2007Yulia A. Kovalitskaya Abstract Synthetic peptide, corresponding to the amino acid sequence 11,24 of human adrenocorticotropic hormone (ACTH), was labeled with tritium (specific activity of 22 Ci/mmol). [3H]ACTH (11,24) was found to bind to rat adrenal cortex membranes with high affinity and specificity (Kd = 1.8 ± 0.1 nM). Twenty nine fragments of ACTH (11,24) have been synthesized and their ability to inhibit the specific binding of [3H]ACTH (11,24) to adrenocortical membranes has been investigated. Unlabeled fragment ACTH 15,18 (KKRR) was found to replace in a concentration-dependent manner [3H]ACTH (11,24) in the receptor,ligand complex (Ki = 2.3 ± 0.2 nM). ACTH (15,18) was labeled with tritium (specific activity of 20 Ci/mmol). [3H]ACTH (15,18) was found to bind to rat adrenal cortex membranes with high affinity (Kd = 2.1 ± 0.1 nM). The specific binding of [3H]ACTH (15,18) was inhibited by unlabeled ACTH (11,24) (Ki = 2.2 ± 0.1 nM). ACTH (15,18) at the concentration range of 1,1000 nM did not affect the adenylate cyclase activity in adrenocortical membranes. Copyright © 2007 European Peptide Society and John Wiley & Sons, Ltd. [source] Synthesis of poly(4-vinylpyridine) by reverse atom transfer radical polymerizationJOURNAL OF POLYMER SCIENCE (IN TWO SECTIONS), Issue 24 2007Gregory T. Lewis Abstract Controlled radical polymerization of 4-vinylpyridine (4VP) was achieved in a 50 vol % 1-methyl-2-pyrrolidone/water solvent mixture using a 2,2,-azobis(2,4-dimethylpentanitrile) initiator and a CuCl2/2,2,-bipyridine catalyst,ligand complex, for an initial monomer concentration of [M]0 = 2.32,3.24 M and a temperature range of 70,80 °C. Radical polymerization control was achieved at catalyst to initiator molar ratios in the range of 1.3:1 to 1.6:1. First-order kinetics of the rate of polymerization (with respect to the monomer), linear increase of the number,average degree of polymerization with monomer conversion, and a polydispersity index in the range of 1.29,1.35 were indicative of controlled radical polymerization. The highest number,average degree of polymerization of 247 (number,average molecular weight = 26,000 g/mol) was achieved at a temperature of 70 °C, [M]0 = 3.24 M and a catalyst to initiator molar ratio of 1.6:1. Over the temperature range studied (70,80 °C), the initiator efficiency increased from 50 to 64% whereas the apparent polymerization rate constant increased by about 60%. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 5748,5758, 2007 [source] Quantitative microscopy reveals 3D organization and kinetics of endocytosis in rat hepatocytesMICROSCOPY RESEARCH AND TECHNIQUE, Issue 9 2006Permsin Marbet Abstract In order to demonstrate the power of quantitative microscopy, the endocytic apparatus of rat hepatocytes was reexamined using in situ liver and short term cultured hepatocyte couplets that were allowed to internalize endocytic markers for various time intervals. Correlative confocal light and electron microscopy demonstrate a tubulovesicular reticulum representing the endocytic apparatus. Volume and membrane area account for 2% of cell volume and 30% plasma membrane surface. Colocalization analysis demonstrated that pathway-specific ligands and fluid-phase markers enter EEA1-positive vesicles, the early endosomal compartment, immediately after internalization. These vesicles are translocated rapidly from basolateral to perinuclear and apical locations. Ligands are sorted within 5 min to their respective pathways. Sequential colocalization of an asialoglycoprotein-pulse with rab7 and lamp3 demonstrates that early endosomes change into or fuse with late endosomes and lysosomes. Alternatively, markers are sequestered into the common endosome consisting of rab11-positive, long tubules that originate from early endosomes and show an affinity for the transcytotic marker pIgA and its receptor. This compartment mediates transcytosis by delivering the receptor,ligand complex to the subapical compartment, a set of apical, rab11-positive vesicles, which are connected to the tubular reticulum. We conclude that vesicular traffic between preexisting compartments, maturation or fusion of endocytic organelles, and transport in tubules act in concert and together mediate transport between compartments of a tubulovesicular endocytic apparatus. In addition, we show that quantitative microscopy using high resolution data sets can detect and characterize kinetics of various parameters thus adding a dynamic component to 3D information. Microsc. Res. Tech., 2006. © 2006 Wiley-Liss, Inc. [source] Comparison of binding energies of SrcSH2-phosphotyrosyl peptides with structure-based prediction using surface area based empirical parameterizationPROTEIN SCIENCE, Issue 10 2000Denise A. Henriques Abstract The prediction of binding energies from the three-dimensional (3D) structure of a protein,ligand complex is an important goal of biophysics and structural biology. Here, we critically assess the use of empirical, solvent-accessible surface area-based calculations for the prediction of the binding of Src-SH2 domain with a series of tyrosyl phosphopeptides based on the high-affinity ligand from the hamster middle T antigen (hmT), where the residue in the pY+3 position has been changed. Two other peptides based on the C-terminal regulatory site of the Src protein and the platelet-derived growth factor receptor (PDGFR) are also investigated. Here, we take into account the effects of proton linkage on binding, and test five different surface area-based models that include different treatments for the contributions to conformational change and protein solvation. These differences relate to the treatment of conformational flexibility in the peptide ligand and the inclusion of proximal ordered solvent molecules in the surface area calculations. This allowed the calculation of a range of thermodynamic state functions (,Cp, ,S, ,H, and ,G) directly from structure. Comparison with the experimentally derived data shows little agreement for the interaction of SrcSH2 domain and the range of tyrosyl phosphopeptides. Furthermore, the adoption of the different models to treat conformational change and solvation has a dramatic effect on the calculated thermodynamic functions, making the predicted binding energies highly model dependent. While empirical, solvent-accessible surface area based calculations are becoming widely adopted to interpret thermodynamic data, this study highlights potential problems with application and interpretation of this type of approach. There is undoubtedly some agreement between predicted and experimentally determined thermodynamic parameters; however, the tolerance of this approach is not sufficient to make it ubiquitously applicable. [source] Structures of apo and GTP-bound molybdenum cofactor biosynthesis protein MoaC from Thermus thermophilus HB8ACTA CRYSTALLOGRAPHICA SECTION D, Issue 7 2010Shankar Prasad Kanaujia The first step in the molybdenum cofactor (Moco) biosynthesis pathway involves the conversion of guanosine triphosphate (GTP) to precursor Z by two proteins (MoaA and MoaC). MoaA belongs to the S -adenosylmethionine-dependent radical enzyme superfamily and is believed to generate protein and/or substrate radicals by reductive cleavage of S -adenosylmethionine using an Fe,S cluster. MoaC has been suggested to catalyze the release of pyrophosphate and the formation of the cyclic phosphate of precursor Z. However, structural evidence showing the binding of a substrate-like molecule to MoaC is not available. Here, apo and GTP-bound crystal structures of MoaC from Thermus thermophilus HB8 are reported. Furthermore, isothermal titration calorimetry experiments have been carried out in order to obtain thermodynamic parameters for the protein,ligand interactions. In addition, molecular-dynamics (MD) simulations have been carried out on the protein,ligand complex of known structure and on models of relevant complexes for which X-ray structures are not available. The biophysical, structural and MD results reveal the residues that are involved in substrate binding and help in speculating upon a possible mechanism. [source] Generating isomorphous heavy-atom derivatives by a quick-soak method.ACTA CRYSTALLOGRAPHICA SECTION D, Issue 7 2002Part II: phasing of new structures A quick-soak method has been applied to generate de novo heavy-atom phasing to solve two new protein structures, a type II transforming growth factor , receptor (TBRII) and a natural killer cell receptor,ligand complex, NKG2D,ULBP3. In the case of TBRII, a crystal derivatized for only 10,min in saturated HgCl2 provided adequate phasing for structure determination. Comparison between HgCl2 derivatives generated by 10,min soaking and by 12,h soaking revealed similar phasing statistics. The shorter soak, however, resulted in a derivative more isomorphous to the native than the longer soak as judged by changes in the unit-cell parameter a upon derivatization as well as by the quality of a combined SIRAS electron-density map. In the case of the NKG2D,ULBP3 structure, all overnight soaks in heavy-atom solutions resulted in crystal lattice disorder and only the quick soaks preserved diffraction. Despite fragile lattice packing, the quick-soaked K2PtCl4 derivative was isomorphous with the native crystal and the electron-density map calculated from combined SIR and MAD phases is better than that calculated from MAD phases alone. Combined with mass-spectrometry-assisted solution heavy-atom derivative screening and the use of synchrotron radiation, the quick-soak derivatization has the potential to transform the time-consuming conventional heavy-atom search into a real-time `on-the-fly' derivatization process that will benefit high-throughput structural genomics. [source] Crystal Structure Analysis and in Silico pKa Calculations Suggest Strong pKa Shifts of Ligands as Driving Force for High-Affinity Binding to TGTCHEMBIOCHEM, Issue 4 2009Tina Ritschel Abstract Expandedlin -benzoguanines exhibit binding affinities to tRNA-guanine transglycosylase (TGT) in the low-nanomolar range. A significant pKa shift is observed for the inhibitors moving from aqueous solution to protein environment. The protonation of the inhibitor facilitates a charge-assisted hydrogen bond in the protein,ligand complex. A novel ligand series is presented to inhibit tRNA-guanine transglycosylase (TGT), a protein with a significant role in the pathogenicity mechanism of Shigella flexneri, the causative agent of Shigellosis. The enzyme exchanges guanine in the wobble position of tRNAAsn,Asp,His,Tyr against a modified base. To prevent the base-exchange reaction, several series of inhibitors have already been designed, synthesized, and tested. One aim of previous studies was to address a hydrophobic pocket with different side chains attached to the parent skeletons. Disappointingly, no significant increase in binding affinity could be observed that could be explained by the disruption of a conserved water cluster. The ligand series examined in this study are based on the known scaffold lin -benzoguanine. Different side chains were introduced leading to 2-amino- lin -benzoguanines, which address a different pocket of the protein and avoid disruption of the water cluster. With the introduction of an amino group in the 2-position, a dramatic increase in binding affinity can be experienced. To explain this significant gain in binding affinity, Poisson,Boltzmann calculations were performed to explore pKa changes of ligand functional groups upon protein binding, they can differ significantly on going from aqueous solution to protein environment. For all complexes, a permanent protonation of the newly designed ligands is suggested, leading to a charge-assisted hydrogen bond in the protein,ligand complex. This increased strength in hydrogen bonding takes beneficial effect on binding affinity of the ligands, resulting in low-nanomolar binders. Crystal structures and docking emphasize the importance of the newly created charge-assisted hydrogen bond. A detailed analysis of the crystal structures in complex with substituted 2-amino- lin -benzoguanines indicate pronounced disorder of the attached side chains addressing the ribose 33 binding pocket. Docking suggests multiple orientations of these side chains. Obviously, an entropic advantage of the residual mobility experienced by these ligands in the bound state is beneficial and reveals an overall improved protein binding. [source] A Resonance Energy Transfer Immunoassay Based on a Thiol-Reactive Ruthenium Donor Dye and a Longwave-Emitting AcceptorCHEMBIOCHEM, Issue 1 2007Jochen Weh Abstract A novel immunoassay is described that applies a thiol-reactive ruthenium metal,ligand complex as the donor dye in a luminescence energy transfer (LET) detection scheme. Unlike amine-reactive labels, the LET with a thiol label allows improved specificity and better reproducibility of labelling positions on proteins, because the number of reactive thiol groups of proteins is distinctly smaller. This helps to reduce the risk of over-labelling and self-quenching of the fluorophore. The synthesis of the thiol label was significantly improved, resulting in almost quantitative yields of pure product. The absorption and emission maxima of the ruthenium donor dye are at 460 nm and 600 nm, respectively, and a Stokes' shift of 140 nm warrants distinct separation of excitation and emission wavelengths even in turbid samples. A cyanine dye with an absorption maximum at 642 nm was chosen as the acceptor label because it has good overlap with the emission spectrum of the donor label. The emission of the acceptor peaks at 660 nm, thus further increasing the Stokes' shift (to an overall 200 nm). The quantification of anti-HSA with the LET immunoassay is possible with this new approach at concentrations as low as 220 pmol,L,1. [source] Convenient Synthesis of Multifunctional EDTA-Based Chiral Metal Chelates Substituted with an S -MesylcysteineCHEMISTRY - A EUROPEAN JOURNAL, Issue 11 2005Andrei Leonov Dr. Abstract We describe the synthetic route to ethylenediaminetetraacetic acid (EDTA) derivatives that can be attached to surface-exposed thiol functional groups of cysteine residues in proteins, via a methylthiosulfonate moiety that is connected in a stereochemically unique way to the C-1 carbon atom of EDTA. Such compounds can be used to align proteins in solution without the need to add liquid crystalline media, and are, therefore, of great interest for the NMR spectroscopic analysis of biomolecules. The binding constant for the paramagnetic tag to lanthanide ions was determined by measuring luminescence. For the Tb+3,ligand complex, a Kb value of 6.5×1017,M,1 was obtained. This value is in excellent agreement with literature values for the related EDTA compound. In addition, it could be shown that there is no significant reduction in the luminescence intensity upon addition of a 104 excess of Ca2+ ions, indicating that this paramagnetic tag is compatible with buffers containing high concentrations of divalent alkaline earth ions. [source] Human telomeric G-quadruplex: The current status of telomeric G-quadruplexes as therapeutic targets in human cancerFEBS JOURNAL, Issue 5 2010Stephen Neidle The 3,-ends of human chromosomal DNA terminate in short single-stranded guanine-rich tandem-repeat sequences. In cancer cells, these are associated with the telomere-maintenance enzyme telomerase together with the end-binding protein hPOT1. Small molecules that can compete with these proteins and induce the single-stranded DNA to form quadruplex,ligand complexes are, in effect, able to expose these 3,-ends, which results in the activation of a DNA damage response and selective inhibition of cell growth. Several of these G-quadruplex binding molecules have shown promising anticancer activity in tumour xenograft models, which indicate that the approach may be applicable to the treatment of a wide range of human cancers. This minireview summarizes the available data on these compounds and the challenges posed for drug discovery. [source] Connectivity and binding-site recognition: Applications relevant to drug designJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 15 2010Christopher J. R. Illingworth Abstract Here, we describe a family of methods based on residue,residue connectivity for characterizing binding sites and apply variants of the method to various types of protein,ligand complexes including proteases, allosteric-binding sites, correctly and incorrectly docked poses, and inhibitors of protein,protein interactions. Residues within ligand-binding sites have about 25% more contact neighbors than surface residues in general; high-connectivity residues are found in contact with the ligand in 84% of all complexes studied. In addition, a k-means algorithm was developed that may be useful for identifying potential binding sites with no obvious geometric or connectivity features. The analysis was primarily carried out on 61 protein,ligand structures from the MEROPS protease database, 250 protein,ligand structures from the PDBSelect (25%), and 30 protein,protein complexes. Analysis of four proteases with crystal structures for multiple bound ligands has shown that residues with high connectivity tend to have less variable side-chain conformation. The relevance to drug design is discussed in terms of identifying allosteric-binding sites, distinguishing between alternative docked poses and designing protein interface inhibitors. Taken together, this data indicate that residue,residue connectivity is highly relevant to medicinal chemistry. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010 [source] A semiempirical free energy force field with charge-based desolvationJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 6 2007Ruth Huey Abstract The authors describe the development and testing of a semiempirical free energy force field for use in AutoDock4 and similar grid-based docking methods. The force field is based on a comprehensive thermodynamic model that allows incorporation of intramolecular energies into the predicted free energy of binding. It also incorporates a charge-based method for evaluation of desolvation designed to use a typical set of atom types. The method has been calibrated on a set of 188 diverse protein,ligand complexes of known structure and binding energy, and tested on a set of 100 complexes of ligands with retroviral proteases. The force field shows improvement in redocking simulations over the previous AutoDock3 force field. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2007 [source] Calculation of affinities of peptides for proteinsJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 3 2004Serena Donnini Abstract Several methodologies were employed to calculate the Gibbs standard free energy of binding for a collection of protein,ligand complexes, where the ligand is a peptide and the protein is representative for various protein families. Almost 40 protein,ligand complexes were employed for a continuum approach, which considers the protein and the peptide at the atomic level, but includes solvent as a polarizable continuum. Five protein,ligand complexes were employed for an all-atom approach that relies on a combination of the double decoupling method with thermodynamic integration and molecular dynamics. These affinities were also computed by means of the linear interaction energy method. Although it generally proved rather difficult to predict the absolute free energies correctly, for some protein families the experimental ranking order was correctly reproduced by the continuum and all-atom approach. Considerable attention has also been given to correctly analyze the affinities of charged peptides, where it is required to judge the effect of one or more ions that are being decoupled in an all-atom approach to preserve electroneutrality. The various methods are further judged upon their merits. © 2003 Wiley Periodicals, Inc. J Comput Chem 25: 393,411, 2004 [source] Application of the frozen atom approximation to the GB/SA continuum model for solvation free energyJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 2 2002Olgun Guvench Abstract The generalized Born/surface area (GB/SA) continuum model for solvation free energy is a fast and accurate alternative to using discrete water molecules in molecular simulations of solvated systems. However, computational studies of large solvated molecular systems such as enzyme,ligand complexes can still be computationally expensive even with continuum solvation methods simply because of the large number of atoms in the solute molecules. Because in such systems often only a relatively small portion of the system such as the ligand binding site is under study, it becomes less attractive to calculate energies and derivatives for all atoms in the system. To curtail computation while still maintaining high energetic accuracy, atoms distant from the site of interest are often frozen; that is, their coordinates are made invariant. Such frozen atoms do not require energetic and derivative updates during the course of a simulation. Herein we describe methodology and results for applying the frozen atom approach to both the generalized Born (GB) and the solvent accessible surface area (SASA) parts of the GB/SA continuum model for solvation free energy. For strictly pairwise energetic terms, such as the Coulombic and van-der-Waals energies, contributions from pairs of frozen atoms can be ignored. This leaves energetic differences unaffected for conformations that vary only in the positions of nonfrozen atoms. Due to the nonlocal nature of the GB analytical form, however, excluding such pairs from a GB calculation leads to unacceptable inaccuracies. To apply a frozen-atom scheme to GB calculations, a buffer region within the frozen-atom zone is generated based on a user-definable cutoff distance from the nonfrozen atoms. Certain pairwise interactions between frozen atoms in the buffer region are retained in the GB computation. This allows high accuracy in conformational GB comparisons to be maintained while achieving significant savings in computational time compared to the full (nonfrozen) calculation. A similar approach for using a buffer region of frozen atoms is taken for the SASA calculation. The SASA calculation is local in nature, and thus exact SASA energies are maintained. With a buffer region of 8 Å for the frozen-atom cases, excellent agreement in differences in energies for three different conformations of cytochrome P450 with a bound camphor ligand are obtained with respect to the nonfrozen cases. For various minimization protocols, simulations run 2 to 10.5 times faster and memory usage is reduced by a factor of 1.5 to 5. Application of the frozen atom method for GB/SA calculations thus can render computationally tractable biologically and medically important simulations such as those used to study ligand,receptor binding conformations and energies in a solvated environment. © 2002 Wiley Periodicals, Inc. J Comput Chem 23: 214,221, 2002 [source] Synthesis of hydroxyl silylated rhenium and (99mTc)technetium ,3+1' mixed ligand complexesJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 8 2002Torsten Kniess Abstract The synthesis of hydroxyl silylated thiols as monodentate ligands is described. These monodentates were used to build with Re and 99mTc trimethyl-, triethyl- and triphenyl-silylated ,3+1' mixed ligand complexes, using 3thiapentane-1,5-dithiol as co-ligand. The Re complexes were characterized by 1H NMR and elemental analysis, the 99mTc complexes were detected by radio HPLC. While the trimethyl silylated derivatives hydrolysed in aqueous media, the triethyl- and triphenyl silylated complexes have proved to be stable in neutral solutions. Copyright © 2002 John Wiley & Sons, Ltd. [source] A molecular recognition paradigm: promiscuity associated with the ligand,receptor interactions of the activin members of the TGF-, superfamilyJOURNAL OF MOLECULAR RECOGNITION, Issue 5 2005Hooi Hong Keah Abstract The structure,function properties of the pleiotropic activins and their relationship to other members of the transforming growth factor-, superfamily of proteins are described. In order to highlight the molecular promiscuity of these growth factors, emphasis has been placed on molecular features associated with the recognition by activin A and the bone morphogenic proteins of the corresponding extracellular domains of the ActRI and ActRII receptors. The available evidence suggests that the homodimeric activin A in its various functional roles has the propensity to fulfill key tasks in the regulation of mammalian cell behaviour, through coordination of numerous transcriptional and translational processes. Because of these profound effects, under physiologically normal conditions, activin A levels are closely controlled by a variety of binding partners, such as follistatin-288 and follistatin-315, ,2 -macroglobulin and other proteins. Moreover, the subunits of other members of the activin subfamily, such as activin B or activin C, are able to form heterodimers with the activin A subunit, thus providing a further avenue to positively or negatively control the physiological concentrations of activin A that are available for interaction with specific receptors and induction of cell signaling events. Based on data from X-ray crystallographic studies and homology modeling experiments, the molecular architecture of the ternary receptor,activin ligand complexes has been dissected, permitting rationalization in structural terms of the pattern of interactions that are the hallmark of this protein family. Copyright © 2005 John Wiley & Sons, Ltd. [source] Metal,Ligand-Containing Polymers: Terpyridine as the Supramolecular UnitMACROMOLECULAR RAPID COMMUNICATIONS, Issue 9-10 2010Raja Shunmugam Abstract New and interesting properties can be obtained from macromolecular architectures functionalized with supramolecular moieties, particularly metal,ligand complexes. Self-assembly, based on the selective control of noncovalent interactions, guides the creation of hierarchically ordered materials providing access to novel structures and new properties. This field has expanded significantly in the last two decades, and one of the most ubiquitous functionalities is terpyridine. Despite its wide-spread use, much basic knowledge regarding the binding of terpyridine with metal ions remains unknown. Here, the binding constants of PEG-substituted terpyridine in relation to other literature reports are studied and a few examples of supramolecular materials from our laboratory are summarized. [source] Side-chain flexibility in protein,ligand binding: The minimal rotation hypothesisPROTEIN SCIENCE, Issue 4 2005Maria I. Zavodszky Abstract The goal of this work is to learn from nature about the magnitudes of side-chain motions that occur when proteins bind small organic molecules, and model these motions to improve the prediction of protein,ligand complexes. Following analysis of protein side-chain motions upon ligand binding in 63 complexes, we tested the ability of the docking tool SLIDE to model these motions without being restricted to rotameric transitions or deciding which side chains should be considered as flexible. The model tested is that side-chain conformational changes involving more atoms or larger rotations are likely to be more costly and less prevalent than small motions due to energy barriers between rotamers and the potential of large motions to cause new steric clashes. Accordingly, SLIDE adjusts the protein and ligand side groups as little as necessary to achieve steric complementarity. We tested the hypothesis that small motions are sufficient to achieve good dockings using 63 ligands and the apo structures of 20 different proteins and compared SLIDE side-chain rotations to those experimentally observed. None of these proteins undergoes major main-chain conformational change upon ligand binding, ensuring that side-chain flexibility modeling is not required to compensate for main-chain motions. Although more frugal in the number of side-chain rotations performed, this model substantially mimics the experimentally observed motions. Most side chains do not shift to a new rotamer, and small motions are both necessary and sufficient to predict the correct binding orientation and most protein,ligand interactions for the 20 proteins analyzed. [source] Binding specificity and the ligand dissociation process in the E. coli biotin holoenzyme synthetasePROTEIN SCIENCE, Issue 3 2002Keehwan Kwon Abstract The binding of the Escherichia coli biotin holoenzyme synthetase to the two ligands, biotin and bio-5,-AMP, is coupled to disorder-to-order transitions in the protein. In the structure of the biotin complex, a "glycine-rich" loop that is disordered in the apo-enzyme is folded over the ligand. Mutations in three residues in this loop result in significant changes in the affinity of the enzyme for both biotin and bio-5,-AMP. The kinetic basis of these losses in the affinity resides primarily in changes in the unimolecular rates of dissociation of the complexes. In this work, isothermal titration calorimetry has been employed to examine the detailed thermodynamics of binding of three loop mutants to biotin and bio-5,-AMP. The energetic features of dissociation of the protein,ligand complexes also have been probed by measuring the temperature dependencies of the unimolecular dissociation rates. Analysis of the data using the Eyring formalism yielded entropic and enthalpic contributions to the energetic barrier to dissociation. The thermodynamic results coupled with the known structures of the apo-enzyme and biotin complex have been used to formulate a model for progression from the ground-state complex to the transition state in biotin dissociation. In this model, the transition-state is characterized by both partial disruption of noncovalent bonds and acquisition of some of the disorder that characterizes the glycine-rich loop in the absence of ligand. [source] Crystallochemical formula as a tool for describing metal,ligand complexes , a pyridine-2,6-dicarboxylate exampleACTA CRYSTALLOGRAPHICA SECTION B, Issue 1 2009Viktor N. Serezhkin Compounds (299) containing 494 symmetrically independent pyridine-2,6-dicarboxylate moieties have been investigated. Among them the structures of Na3[Nd(Pydc)3]·14H2O and Na3[Er(Pydc)3]·11.5H2O, where H2Pydc is pyridine-2,6-dicarboxylic acid, were determined by single-crystal X-ray diffraction, while the others were taken from the Cambridge Structural Database. The characteristics of any complex by means of the `method of crystallochemical analysis' are described, and the coordination types of all the Pydc ions and crystallochemical formulae of all the compounds were determined. Although the ion can act as a mono-, bi-, tri-, tetra- and pentadentate ligand, 96% of Pydc ions are coordinated to the central A atom in the tridentate-chelating mode. The dependence of the denticity and geometry of pyridine-2,6-dicarboxylate, as well as of the composition of Pydc-containing complexes, was studied as a function of the nature of the A atom, the molar ratio Pydc:A and the presence of neutral or acidic ligands in the reaction mixture. [source] Synthetic, spectral as well as in vitro antimicrobial studies on some bismuth(III) bis(N,N -dialkyldithiocarbamato) alkylenedithiophosphatesAPPLIED ORGANOMETALLIC CHEMISTRY, Issue 4 2010H. P. S. Chauhan Abstract Mixed sulfur donor ligand complexes of the type bismuth(III) bis(N,N -dialkyldithiocarbamato) alkylenedithiophosphate, [R2NCS2]2BiS2POGO [where R = CH3 and C2H5; G = -CH2 -C(C2H5)2 -CH2 -, -CH2 -C(CH3)2 -CH2 -, -CH(CH3)-CH(CH3)- and -C(CH3)2 -C(CH3)2 -] were synthesized in 1:1 molar ratio of bismuth(III) bis(N,N -dialkyldithiocarbamate) chloride and ammonium alkylenedithiophosphate in refluxing benzene and characterized by melting point, molecular weight determinations, elemental analysis (C, H, N, Bi and S) and spectral [UV, IR,NMR (1H,13C and 31P) and powder X ray diffraction] studies; all these studies were in good agreement with the synthesized complexes. These newly synthesized derivatives are yellow and brown colored solids and are soluble in common organic solvents like benzene, chloroform, dichloromethane and DMF. Based on the physicochemical and spectral studies, a tentative structure of these newly synthesized complexes was assigned and the average particle size of the synthesized complexes determined by powder XRD, showing that nano range polycrystalline particles were formed with a monoclinic crystal system. These complexes were also screened for their antimicrobial activities using the well diffusion method. The free ligands as well as their mixed metal complexes were tested in vitro against four bacterial strains: two Gram-positive, Staphylococcus aureus (ATCC 9144) (G+) and Bacillus subtilis (ATCC 6051), (G+) and two Gram-negative, Escherichia coli (ATCC 9637) (G,) and Pseudomonas aeruginosa (ATCC 25619) (G,) to assess their antimicrobial properties. The results were indeed positive and exhibited good antibacterial effects. Chloroamphenicol used as a standard for comparison and synthesized complexes showed good antibacterial effects over chloroamphenicol. On the basis of these studies, the synthesized complexes help to understand the different structural and biological properties of main group elements with sulfur donor ligands. Copyright © 2010 John Wiley & Sons, Ltd. [source] Antibacterial, spectral and thermal aspects of drug based-Cu(II) mixed ligand complexesAPPLIED ORGANOMETALLIC CHEMISTRY, Issue 10 2009G. J. Kharadi Abstract The antibiotic agent clioquinol is well known for its drug design and coordinating ability towards metal ions. Copper(II) mixed-ligand complexes of clioquinol with various uninegative bidentate ligands were prepared. The structure of the synthesized complexes was characterized using elemental analyses, infrared spectra, 1H-NMR spectra, electronic spectra, magnetic measurements, FAB mass spectrum and thermo gravimetric analyses. The kinetic parameters such as order of reaction (n) and the energy of activation (Ea) are reported using the Freeman,Carroll method. The pre-exponential factor (A), the activation entropy (,S#), the activation enthalpy (,H#) and the free energy of activation (,G#) were calculated. Complexes were also screened for their in vitro antibacterial activity against a range of Gram-positive and Gram-negative bacteria in order to set the precursors for anti-tumourigenic agent. Copyright © 2009 John Wiley & Sons, Ltd. [source] Cross-linking of protein crystals as an aid in the generation of binary protein,ligand crystal complexes, exemplified by the human PDE10a,papaverine structureACTA CRYSTALLOGRAPHICA SECTION D, Issue 8 2009Ole Andreas Andersen Protein crystallography has proven to be an effective method of obtaining high-resolution structures of protein,ligand complexes. However, in certain cases only apoprotein structures are readily available and the generation of crystal complexes is more problematic. Some crystallographic systems are not amenable to soaking of ligands owing to crystal-packing effects and many protein,ligand complexes do not crystallize under the same conditions as used for the apoprotein. Using crystals of human phosphodiesterase 10a (hPDE10a) as an example of such a challenging crystallographic system, the structure of the complex with papaverine was obtained to 2.8,Å resolution using protein crystals cross-linked by glutaraldehyde prior to soaking of the ligand. Inspection of the electron-density maps suggested that the correct mode of binding was obtained in one of the two monomers in the asymmetric unit and inspection of crystal-packing contacts explained why cocrystallization experiments and soaking of crystals that were not cross-linked were unsuccessful. [source] Structures of Arthrobacter globiformis urate oxidase,ligand complexesACTA CRYSTALLOGRAPHICA SECTION D, Issue 8 2008Ella Czarina Magat Juan The enzyme urate oxidase catalyzes the conversion of uric acid to 5-hydroxyisourate, one of the steps in the ureide pathway. Arthrobacter globiformis urate oxidase (AgUOX) was crystallized and structures of crystals soaked in the substrate uric acid, the inhibitor 8-azaxanthin and allantoin have been determined at 1.9,2.2,Å resolution. The biological unit is a homotetramer and two homotetramers comprise the asymmetric crystallographic unit. Each subunit contains two T-fold domains of ,,,,,, topology, which are usually found in purine- and pterin-binding enzymes. The uric acid substrate is bound tightly to the enzyme by interactions with Arg180, Leu222 and Gln223 from one subunit and with Thr67 and Asp68 of the neighbouring subunit in the tetramer. In the other crystal structures, lithium borate, 8-azaxanthin and allantoate are bound to the enzyme in a similar manner as uric acid. Based on these AgUOX structures, the enzymatic reaction mechanism of UOX has been proposed. [source] Crystallization to obtain protein,ligand complexes for structure-aided drug designACTA CRYSTALLOGRAPHICA SECTION D, Issue 6 2006Dennis E. Danley The use of X-ray crystallography to derive three-dimensional structures for structure-aided drug design (SADD) is a common activity in drug discovery today. In this process, the structures of inhibitors or other ligands of interest complexed with their macromolecular target are solved and the structural information is used iteratively to design new molecules. The ability to form cocrystal complexes between a target protein and a ligand is essential to this process and therefore is of considerable interest to anyone practicing in this field. In the course of obtaining the necessary ligand,protein crystals, even with crystallization conditions well established for a protein of interest, obtaining co-structures with inhibitors either through cocrystallization or soaking is too often not successful. There are numerous potential reasons for this lack of success and this article outlines a number of possible factors that may be involved and discusses considerations that should be taken into account when designing successful experiments to obtain iterative costructures. [source] | |||||||||||||||||||