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PubMed2000

Molecular modelling and conformational analysis of novel glycoprotein (Gp) IIb/IIIa antagonists. Molecular orbital calculation and the condensed heterocyclic derivatives.

A naphthalene compound was chosen as lead compound to develop a new series of fibrinogen receptor antagonists. Eight new compounds with different condensed heterocyclic parts were prepared and their in vitro activities were evaluated. 5-Amidinobenzofuran compound 2, 6-amidinobenzothiophene 7, and 5-amidinofuro[2,3-b]pyridine 8 were more active than lead compound 1. Molecular orbital calculation studies suggested the presence of a preferred spatial orientation between the amidine and the carboxylic acid.

Acetates↗
PubMed2005

RuII complexes incorporating tetrathiamacrocycles: synthesis and conformational analysis.

The synthesis of a series of RuII complexes incorporating thiacrown ligands ([12]ane-S4, [14]ane-S4, [16]ane-S4), as well as 2,2'-bipyridine (bpy) or pyridine, is reported. Structural studies on these complexes have been carried out using a variety of techniques. Detailed 1H NMR spectroscopic studies on the previously reported [Ru([12]ane-S4)(bpy)]2+ (1) reveal that-contrary to earlier reports-the observed fluxional 1H NMR behavior is not due to chemical exchange involving cleavage of the bpy Ru--N bond but is, in fact, due to lone-pair inversion of coordinated macrocyclic sulfur donor atoms. This phenomenon is also observed for the [14]ane-S4 and [16]ane-S4 analogues of 1. For the first time, using a combination of X-ray crystallography, more detailed 1H NMR experiments, and computational methods, an in-depth study on the energetics and dynamics of invertomer formation and conversion for macrocyclic coordination complexes has been carried out. These studies reveal that the steric constraints of assembling each sulfur macrocycle and bpy ligand around the octahedral Ru(II) center lead to close intramolecular contacts. These contacts are largely dependent on the orientation of the electron lone pairs of equatorial sulfur donor atoms and correlate with the comparative stability of the different invertomeric forms. Thus, the conformational preferences of the three macrocyles in [Ru([n]ane-S4)(bpy)]2+ complexes are determined by steric rather than electronic effects.

Crystallography, X-Ray↗
PubMed1976

Conformational analysis of deoxyribonucleic acid from PM2 bacteriophage. The effect of size on supercoil shape.

Laser light-scattering studies of bacteriophage PM2 DNA showed the molecule to have mol.wt. 5.9 X 10(6) and root-mean -square radius 125 nm at an ionic strength of 0.2 mol/litre. Computer-generated curves compatible with these data were compared with the experimental interference curve for several structural models of the molecules. The data fit best to an asymmetric four-armed planar molecule in which all four arms emerge from or close to the one area of the molecule. This contrasts with the smaller DNA molecules investigated, which have shown a three-armed molecule, whose symmetry varies with primary structure.

Bacteriophages↗
PubMed2000

Boat conformations. Analysis and simulation of the complex 1H NMR spectrum of methyl 2,6:3,4-dianhydro-alpha-D-altropyranoside.

The complex 1H NMR spectrum of methyl 2,6:3,4-dianhydro-alpha-D-altropyranoside (1) has been analyzed and simulated in detail by using input parameters derived from experimental 1H chemical shifts, long- and short-range coupling constants, spin-lattice relaxation times, and effective, spin-spin relaxation times obtained by trial and error matching of the experimental and simulated spectra. The 13C spin-lattice relaxation times of 1 have also been measured, and along with the 1H-1H long- and short-range coupling constants, have been interpreted in terms of the geometry of 1 defined by molecular dynamics with simulated annealing.

Anhydrides↗
PubMed1988

Conformational analysis of 16 S ribosomal RNA from Escherichia coli by scanning transmission electron microscopy.

Digitized images of molecules of 16 S rRNA from Escherichia coli, obtained by scanning transmission electron microscopy (STEM), provide quantitative structural information that is lacking in conventional electron micrographs. We have determined the morphology, total molecular mass, mass distribution within individual rRNA molecules and apparent radii of gyration. From the linear density (M/L) we have assessed the number of strands in the structural backbone of rRNA and studied the pattern of branching and folding related to the secondary and tertiary structure of rRNAs under various buffer conditions. Even in reconstitution buffer 16 S RNA did not show any resemblance to the native 30 S subunit.

Escherichia coli↗
PubMed1999

Conformational analysis of the major DNA adduct derived from the food mutagen 2-amino-3-methylimidazo[4,5-f]quinoline.

The heterocyclic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) is one of a number of carcinogens found in barbecued meat and fish. It is mutagenic in bacterial and mammalian assays and induces tumors in mammals. IQ is biochemically activated to a derivative which reacts with DNA to form a major covalent adduct at carbon 8 of guanine. This adduct may deform the DNA and consequently cause a mutation, which may be responsible for initiating IQ's carcinogenicity. Atomic resolution structures of the IQ-damaged DNA are not yet available experimentally. We have carried out an extensive molecular mechanics energy minimization search to locate feasible structures for the major IQ-DNA adduct in the representative sequence d(5'-G1-G2-C3-G4-C5-C6-A7-3'). d(5'-T8-G9-G10-C11-G12-C13-C14-3') with IQ modification at G4; this contains the GGCGCC mutational hotspot sequence known as NarI. The molecular mechanics program AMBER 5.0 with the force field of Cornell et al. [(1995) J. Am. Chem. Soc. 117, 5179-5197] was employed, including explicit Na(+) counterions and an implicit treatment for solvation. However, key parameters, the partial charges, bond lengths, bond angles, and dihedral parameters of the modified residue, are not available in the AMBER database. We carefully parametrized the force field, created 800 starting conformations which uniformly sampled at 18 degrees intervals each of the three flexible torsion angles that govern the IQ-DNA orientation, and minimized their energy. A conformational mix of structural types, including major groove, minor groove, and base-displaced intercalated carcinogen positions, was generated. This mixture may be related to the diversity of mutational outcomes induced by IQ.

Chemical Phenomena↗
PubMed1991

Conformational analysis of two cyclic disulfide peptides.

Complete nmr and CD studies of two cyclic tetrapeptides with disulfide bonds, Ac-L-Pen-L-Pro-D-Val-L-Cys-NH2 (1) and Ac-L-Cys-L-Pro-D-Val-L-Cys-NH2 (2) bonds have been carried out in different solvents to investigate the formation and stabilization of beta-turn structures and to determine the stereochemistry of the disulfide linkage. Both peptides have three-dimensional structures with a type II beta-turn, as derived from quantitative nuclear Overhauser effect data. The combined use of CD and nmr indicates that the dihedral angle of the disulfide bridge is different in the two peptides, although the chirality is maintained.

Amino Acid Sequence↗
PubMed1995

Conformational analysis of disaccharides using molecular dynamics and NMR methods.

The internal dynamics of four disaccharides, a galacturonic acid dimer, beta-ethyl-lactoside, sucralose and arabinobiose, have been studied using molecular dynamics and nuclear magnetic resonance methods. Theoretical motion models, which include order parameters and correlation times for internal motions, were extracted from dynamics trajectories in vacuo. In parallel, theoretical NOESY volumes were calculated from averaged distance matrices using 'model-free' spectral densities. These data were least-squares fitted to the normalized experimental NOESY volumes using the order parameters and internal motion correlation times as adjustable parameters. The resulting 'experimental' motional models were in good agreement with the theoretical ones with the exception of the galacturonic acid dimer which was best described by the rigid molecule approximation.

Carbohydrate Conformation↗
PubMed1997

Crystal structure of an oligomer of proteolytic zymogens: detailed conformational analysis of the bovine ternary complex and implications for their activation.

The pancreas of ruminants secretes a 100 kDa non-covalent ternary complex of the zymogen of a metalloexopeptidase, carboxypeptidase A, and the proforms of two serine endopeptidases, chymotrypsin C and proteinase E. The crystal structure of the bovine complex has been solved and refined to an R-factor of 0.192 using synchrotron radiation X-ray data to 2.35 A resolution. In this heterotrimeric complex, the 403 residue procarboxypeptidase A takes a central position, with chymotrypsinogen C and proproteinase E attached to different surface sites of it. The procarboxypeptidase A subunit is composed of the active enzyme part and the 94 residue prodomain, similar to the monomeric porcine homologous form. The 251 residue subunit chymotrypsinogen structure, the first solved of an anionic (acidic pI) chymotrypsinogen, exhibits characteristics of both chymotrypsinogen A and elastases, with a potential specificity pocket of intermediate size (to accommodate apolar medium-sized residues) although not properly folded, as in bovine chymotrypsinogen A; this pocket displays a "zymogen triad" characteristic for zymogens of the chymotrypsinogen family, consisting of three non-catalytic residues (one serine, one histidine, and one aspartate) arranged in a fashion similar to the catalytic residues in the active enzymes. Following the traits of this family, the N terminus is clamped to the main molecular body by a disulphide bond, but the close six residue activation segment is completely disordered. The third zymogen, the 253 residue proproteinase E, bears close conformational resemblance to active porcine pancreatic elastase; its specificity pocket is buried, displaying the second "zymogen triad". Its five N-terminal residues are disordered, although the close activation site is fixed to the molecular surface. The structure of this native zymogen displays large conformational differences when compared with the recently solved crystal structure of bovine subunit III, an N-terminally truncated, non-activatable, proproteinase E variant lacking the first 13 residues of the native proenzyme. Most of the prosegment of procarboxypeptidase A and its activation sites are buried in the centre of the oligomer, whilst the activation sites of chymotrypsinogen C and proproteinase E are surface-located and not involved in intra or inter-trimer contacts. This organization confers a functional role to the oligomeric structure, establishing a sequential proteolytic activation for the different zymogens of the complex. The large surface and number of residues involved in the contacts among subunits, as well as the variety of non-bonded interactions, account for the high stability of the native ternary complex.

Animals↗
PubMed1994

Solid-phase synthesis, conformational analysis and in vitro cleavage of synthetic human synaptobrevin II 1-93 by tetanus toxin L chain.

A 93-residue peptide corresponding to the cytosolic domain of a human vesicle associated membrane protein (VAMP or synaptobrevin) has been prepared by solid-phase peptide synthesis in order to investigate the proteolytic activity of the tetanus toxin light chain (TeTx L chain). This protein has been recently reported to inactivate the neuronal rat synaptobrevin II by proteolysis. We show in this study that the synthetic human synaptobrevin II 1-93 (Syb II 1-93) as well as an N-terminus-shortened 69-residue peptide (Syb II 25-93) were cleaved selectively at the Gln76-Phe77 peptide bond by TeTx L chain while shorter peptides were not. A Michaelis constant Km = 192 +/- 2 microM and a catalytic constant kcat = 0.5 min-1 were found for the 93-residue peptide. A neutral optimum pH for the cleavage rate, an inhibition by preincubation of the toxin with well known nonspecific inhibitors of metallopeptidases as well as a zinc-dependent enzyme activity suggest that TeTx belongs to the zinc endopeptidase family. Moreover an activation by reducing agents and an inhibition by cysteine-modifying chemical reagents indicate a critical thiol dependency. Among several specific inhibitors of zinc endopeptidases tested, none could inhibit TeTx L chain even at high concentration. Structural studies by 600-MHz 1H-NMR showed that in water or dimethylsulfoxide the peptide Syb II 1-93 and shorter fragments did not present well defined conformations. Nevertheless protein-protein interactions have been shown for the peptides Syb II 1-93 and 25-93 but not for Syb II 51-93, a fragment not cleaved by TeTx L chain.

Amino Acid Sequence↗
PubMedDate not supplied

Synthesis and conformation analysis of 3-substituted derivatives of 1H,3H-pyrido[2,3-d] pyrimidin-4-one of expected depressive nervous system. Part III.

Four series of new 1-aryl (heteroaryl) piperazinylacetyl derivatives of 1H,3H-pyrido[2,3-d] pyrimidin-4-one VIIa-o were synthesised. Substrates for the synthesis of VIa-d were obtained from the respective 3H-pyrido[2.3-d]pyrimidines IVa-d in the reaction with NaBH4. Compounds VIa-d were prepared by chloroacetylation. The obtained 1-chloroacetyl derivatives in the reaction with respective aryl (heteroaryl) piperazine formed 1-aminoacetyl derivatives of 2-phenyl-1 H.3H-pyrido[2.3-d]pyrimidin-4-one compounds VII1a-n. The structure ol compounds was analysed by 1H, 13C NMR spectroscopy.

Central Nervous System Depressants↗
PubMed1989

Structure and conformational analysis of lipid-associating peptides of apolipoprotein B-100 produced by trypsinolysis.

Apolipoprotein B-100 (apo B-100) contains putative lipid-associating regions that are, in part, responsible for its overall structure in human plasma low-density lipoproteins. Some of these regions have been identified by reassembly of the total tryptic peptides of apo B-100 with bovine brain sphingomyelin, 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC) and dimyristoylphosphatidylcholine (DPMC). Although more than 500 tryptic peptides are predicted from the known number of arginines and lysines in apo B-100, significant amounts of only 13 peptides spontaneously associate with all three phospholipids. These peptides share some structural characteristics, as predicted by several algorithms, that distinguish them from the water-soluble apolipoproteins. Most apolipoproteins associate with lipids via amphipathic helices and are highly helical in native and reassembled lipoproteins. Analysis of all apo B-100 lipophilic peptides by circular dichroism and by use of a predictive algorithm reveals no evidence of amphipathic helices. Although the predictive algorithm suggested that the lipophilic peptides of apo B-100 contain the sequence determinants for beta-sheet, no spectroscopic evidence for this structure was found. We conclude that the lipophilic regions of apo B-100 liberated by trypsinolysis are highly hydrophobic, although their secondary structures do not fit any simple model.

Amino Acid Sequence↗
PubMed2006

Synthesis and conformational analysis of Id2 protein fragments: impact of chain length and point mutations on the structural HLH motif.

The Id proteins are negative regulators of several basic-helix-loop-helix (HLH) transcription factors, including the ubiquitous E factors and the tissue-specific myogenin-regulating factors. Id1 through Id4 contain highly identical HLH domains but different N- and C-terminal extensions. Beside the heterodimerization with the parent HLH factors, Id2 was shown to additionally interact with the retinoblastoma protein and to be overexpressed in neuroblastoma. Thus, Id2 represents an interesting target for cancer therapy based on the inhibition of protein-protein interactions. Here we present the synthesis and circular dichroism (CD) analysis of peptides derived from point mutations and N-/C-terminal truncations of Id2. The helix character of the HLH domain (residues 36-76) was reduced upon substitution of Met39/-62 and Cys42 with Nle and Ser, respectively, suggesting a structural role of these side chains. The largest sequence that could be obtained by stepwise solid-phase peptide synthesis (SPPS) with Fmoc strategy spanned the entire HLH motif (with Cys42 replaced by Ser) and part of the C-terminus (residues 77-110). This 75-residue long fragment was less helical than the isolated HLH domain and had propensity to aggregate, which was correlated with the presence of the flanking residues C-terminal to helix-2. By CD analysis of an equimolar mixture of the sequence 36-110 with the N-terminus 1-35, noncovalent interactions between the two peptides were detected, which, however, changed upon aging. In contrast, the mixture of the HLH sequence 36-76 with the N-terminus was characterized by a stabilized helix structure that was maintained also upon aging. Presumably, the N-terminal region interacted with the folded HLH motif in a specific manner, whereas only unspecific, weak contacts occurred with the partly unfolded HLH domain and/or the immediate flanking residues 77-110.

Amino Acid Sequence↗
PubMed2006

Dynamic light scattering, interfacial properties, and conformational analysis of biodegradable quarternary ammonium surfactants.

Aggregation properties of biodegradable ammonium surfactants containing amide and ester groups in the bulk and at the air-water interface were investigated as a function of surfactant tail length m using dynamic light scattering and surface tension experimental methods. The results indicate that surfactants containing an ester group in the structure display higher aggregation ability in the volume and form more densely packed layer of molecules at the air-water interface than those with an amide group. The results of physical measurements were correlated with 3D models of respective surfactant molecules. As the results indicate, a surfactant molecule headgroup containing an ester group shows higher flexibility than that with an amide group in its structure, which is documented by somewhat smaller headgroup size and denser packing at the air-water interface.

Alkylation↗
PubMed2006

Conformational analysis in solution of gastrin releasing peptide.

Gastrin releasing peptide (GRP) is the first peptide isolated from porcine gastric and intestinal tissues and is homologous to the carboxyl terminus of bombesin (Bn) isolated from the skin of the frog Bombina bombina. It is a member of the Bn-like peptides, which are important in numerous biological and pathological processes. The Bn-like peptides show high sequence homology in their C-terminal regions, but they have different selectivity for their receptors. In particular, GRP selectively binds to the GRP receptor (GRPR). However, the molecular basis for this selectivity remains largely unknown. Here, we report the three-dimensional structure of GRP. Hopefully, it could be helpful in a better understanding of the binding selectivity between GRP and GRPR.

Amino Acid Sequence↗
PubMed2006

Highly enantioselective synthesis of atropisomeric anilide derivatives through catalytic asymmetric N-arylation: conformational analysis and application to asymmetric enolate chemistry.

In the presence of (R)-DTBM-SEGPHOS-Pd(OAc)(2) catalyst, N-arylation (aromatic amination) of various o-tert-butylanilides with p-iodonitrobenzene proceeds with high enantioselectivity (88-96% ee) to give atropisomeric N-(p-nitrophenyl)anilides having an N-C chiral axis in good yields. Atropisomeric anilide products highly prefer to exist as the E-rotamer which has trans-disposed o-tert-butylphenyl group and carbonyl oxygen. The application of the present catalytic enantioselective N-arylation to an intramolecular version gives atropisomeric lactam derivatives with high optical purity (92-98% ee). The reaction of the lithium enolate prepared from the atropisomeric anilide and lactam products with various alkyl halides gives alpha-alkylated products with high diastereoselectivity (diastereomer ratio = 13:1 to 46:1).

Amination↗
PubMed1986

Conformational analysis of hairpin oligodeoxyribonucleotides by a single-strand-specific nuclease.

Hairpin-forming oligodeoxynucleotides d[ATCCTA(A)NTAGGAT] with n = 3-6 were subjected to nuclease digestion with the nuclease from mung bean. Cleavage occurs only in the loop region of the hairpin molecules. In detail, the number and intensity of cleavage sites were determined in relation to the length of the loop, the temperature and the salt concentration. The restricted accessibility of mung bean nuclease to the loop bases adjacent to the helical region of all hairpins is due to a reduced exposure of these bases in presence of a certain Mg2+ concentration. With increasing temperature the exposure of these bases is increased. It is deduced that the bases adjacent to the helix increase the length of the latter by stacking, the degree of which is dependent on the number of loop bases.

Binding Sites↗
PubMed1997

Isolation and conformational analysis of fragment peptide corresponding to the heparin-binding site of hepatocyte growth factor.

Hepatocyte growth factor (HGF) is a potent mitogen for hepatocytes. The mitogenic activity of HGF is mediated by its binding to a high-affinity receptor, c-Met. Heparan sulfate is an initial binding site for HGF, based on its relative abundance on the cell surface. The binding of HGF to heparin or heparin-like molecules may induce oligomerization of HGF and facilitate c-Met-dependent mitogenesis [Zioncheck et al. (1995) J. Biol.Chem. 270, 16871-16878]. Thus, heparin binding is important for the biological activity of HGF. To identify the heparin-binding site of HGF, we isolated fragment peptides corresponding to the site by limited proteolysis and chemical degradation of recombinant human HGF (rhHGF). The heparin-binding ability of the peptides was expressed as their elution positions on heparin-affinity column chromatography with NaCl gradient elution. Because all of the heparin-binding peptides obtained in this study were isolated from the N-terminal hairpin-loop region (PyrGlu32-Asn127) of HGF, the region was identified as the heparin-binding site of HGF. One of the isolated peptides, Phe42-Glu111, containing the N-terminal hairpin-loop structure, was considered a suitable model peptide for the heparin-binding site of HGF. From the observation using circular dichroism spectroscopy, it was indicated that the secondary structure of the peptide changed from a random structure to a beta-sheet-like structure upon heparin binding. In addition, oligomerization of HGF in the presence of heparin was observed by dynamic light scattering. Based on our evidence, it is considered that the conformational change in the heparin-binding site may induce the oligomerization of HGF.

Amino Acid Sequence↗