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At least 649 records · Page 36Linked to original sources
PubMed1997

Conformational analysis of galanin using end to end distance distribution observed by Förster resonance energy transfer.

The structural dynamics of the flexible neuropeptide galanin in solution were studied by Förster resonance energy transfer measurements at different temperatures by time-resolved fluorescence spectroscopy to determine its conformational heterogeneity. Endogenous tryptophan at position 2 acted as the fluorescent donor and the non fluorescent acceptor dinitrophenyl or the fluorescent acceptor dansyl were selectively attached to lysine 25 in porcine galanin. The coexistence of different structures of the neuropeptide galanin in trifluoroethanol solution was revealed by the model independent analysis of the distribution of relaxation times from the time-resolved resonance energy transfer data. Multiple conformational states are reflected by distinct end-to-end distance populations. The conformations differ in mean donor-acceptor distance by about 15, and are consistent with the extended and folded backbone conformations of two alpha-helical regions separated by a flexible hinge. The effect that the labelling of galanin has on binding to the receptor was also evaluated. DNP-galanin showed the same high affinity to galanin receptors as unlabelled galanin, whereas DNS-galanin had significantly reduced affinity.

Chemical Phenomena↗
PubMed1999

Structural consequences of the B5 histidine --> tyrosine mutation in human insulin characterized by X-ray crystallography and conformational analysis.

The addition of phenols to hexameric insulin solutions produces a particularly stable hexamer, resulting from a rearrangement in which residues B1-B8 change from an extended conformation (T-state) to form an alpha-helix (R-state). The R-state is, in part, stabilized by nonpolar interactions between the phenolic molecule and residue B5 His at the dimer-dimer interface. The B5 His --> Tyr mutant human insulin was constructed to see if the tyrosine side chain would mimic the effect of phenol binding in the hexamer and induce the R-state. In partial support of this hypothesis, the molecule crystallized as a half-helical hexamer (T(3)R(3)) in conditions that conventionally promote the fully nonhelical (T6) form. As expected, in the presence of phenol or resorcinol, the B5 Tyr hexamers adopt the fully helical (R6) conformation. Molecular modeling calculations were performed to investigate the conformational preference of the T-state B5 Tyr side chain in the T(3)R(3) form, this side chain being associated with structural perturbations of the A7-A10 loop in an adjacent hexamer. For an isolated dimer, several different orientations of the side chain were found, which were close in energy and readily interconvertible. In the crystal environment only one of these conformations remains low in energy; this conformation corresponds to that observed in the crystal structure. This suggests that packing constraints around residue B5 Tyr result in the observed structural rearrangements. Thus, rather than promoting the R-state in a manner analogous to phenol, the mutation appears to destabilize the T-state. These studies highlight the role of B5 His in determining hexamer conformation and in mediating crystal packing interactions, properties that are likely be important in vivo.

Amino Acid Substitution↗
PubMed2004

Conformational analysis and assignments of relative stereocenter configurations in fluoroalkyl-iridium complexes using 19F[1H] HOESY experiments. Comparison with solid-state X-ray structural results.

Solution conformations about the metal-carbon bond of the secondary fluoroalkyl ligands in iridium complexes [IrCp(PMe(3))(R(F))X] [Cp* = C(5)Me(5); R(F) = CF(CF(3))(2), X = I (1), CH(3) (2); R(F) = CF(CF(3))(CF(2)CF(3)), X = I (4), CH(3) (5)] have been determined using (19)F[(1)H] HOESY techniques. The molecules adopt the staggered conformation with the tertiary fluorine in the more hindered sector between the PMe(3) and X ligands, with CF(3) (and CF(2)CF(3)) substituents lying in the less hindered regions between PMe(3) and Cp or X and Cp. In molecules containing the CF(CF(3))(2) ligand, these conformations are identical to those adopted in the solid state. For compound 4, containing the CF(CF(3))(CF(2)CF(3)) ligand, two diastereomers are observed in solution. Solution conformations and relative stereocenter configuration assignments have been obtained using (19)F[(1)H] HOESY and correlated with the X-ray structure for the major diastereomer of 4, which has the (S(Ir), S(C)) or (R(Ir), R(C)) configuration. Relative stereocenter configurations of analogue 5, for which no suitable crystals could be obtained, were assigned using (19)F[(1)H] HOESY and proved to be different from 4, with 5 preferring the (S(Ir), R(C)) or (R(Ir), S(C)) configuration.

Journal Article↗
PubMed2001

Quantitative conformational analysis of the core region of N-glycans using residual dipolar couplings, aqueous molecular dynamics, and steric alignment.

A method is described for quantitatively investigating the dynamic conformation of small oligosaccharides containing an alpha(1 --> 6) linkage. It was applied to the oligosaccharide Man-alpha(1 --> 3) [Man-alpha(1 --> 6)] Man-alpha-O-Me, which is a core region frequently observed in N-linked glycans. The approach tests an aqueous molecular dynamics simulation, capable of predicting microscopic dynamics, against experimental residual dipolar couplings, by assuming that alignment is caused purely by steric hindrance. The experimental constraints were heteronuclear and homonuclear residual dipolar couplings, and in particular those within the alpha(1 --> 6) linkage itself. Powerful spin-state-selective pulse sequences and editing schemes were used to obtain the most relevant couplings for testing the model. Molecular dynamics simulations in water over a period of 50 ns were not able to predict the correct rotamer population at the alpha(1 --> 6) linkage to agree with the experimental data. However, this sampling problem could be corrected using a simple maximum likelihood optimisation, indicating that the simulation was modelling local dynamics correctly. The maximum likelihood prediction of the residual dipolar couplings was found to be an almost equal population of the gg and gt rotamer conformations at the alpha(1--> 6) linkage, and the tg conformation was predicted to be unstable and unpopulated in aqueous solution. In this case all twelve measured residual dipolar couplings could be satisfied. This conformer population could also be used to make predictions of scalar couplings with the use of a previously derived empirical equation, and is qualitatively in agreement with previous predictions based on NMR, X-ray crystallography and optical data.

Carbohydrate Conformation↗
PubMed2004

Adenophostin A and analogues modified at the adenine moiety: synthesis, conformational analysis and biological activity.

The synthesis of adenophostin A (2) and two analogues [etheno adenophostin (4) and 8-bromo adenophostin (5)] modified at the adenine moiety, is reported. A combination of NMR analysis and molecular modelling was used to compare their structures in solution and determined that they all adopt very similar conformations. The analogues were tested for their ability to mobilise Ca(2+) from DT40 cells expressing recombinant Type 1 rat Ins(1,4,5)P(3)R which reveals etheno adenophostin as a high affinity fluorescent probe of the Ins(1,4,5)P(3)R. 8-Bromo adenophostin was only slightly less potent. The biological results support our current hypothesis regarding the binding mode of adenophostin A at the Ins(1,4,5)P(3)R, i. e. that a cation-pi interaction between the base moiety and Arg 504 of the receptor in combination with H-bonding may be responsible for the high potency of adenophostin A relative to Ins(1,4,5)P(3).

Adenine↗
PubMed1986

Haloperidol binding to monoclonal antibodies: conformational analysis and relationships to D-2 receptor binding.

A library of 22 monoclonal antibodies to the D-2 dopaminergic receptor antagonist haloperidol has been developed by immunizing BALB/c mice with two conformationally distinct immunogens. The two immunogens were prepared by coupling haloperidol to bovine serum albumin through the tertiary alcohol at the 4-position of the piperidine ring with a succinic acid linkage and by coupling to bovine serum albumin through the ketone group of the butyrophenone with a carboxymethyl oxime linkage. Seventeen monoclonal antibodies displayed specific, saturable, high affinity binding of [3H]haloperidol which could be inhibited by a variety of neuroleptic drugs. Three monoclonal antibodies raised against the succinic acid conjugate and two monoclonal antibodies raised against the oxime conjugate were selected for detailed analysis of the molecular characteristics of binding specificity and for relationships to bovine striatal D-2 dopaminergic receptor binding. The monoclonal antibody with highest affinity for haloperidol, 185(2)-1 (raised against the succinic acid conjugate and herein referred to as mAb A), had a Kd of 3.3 (+/- 0.06) nM and primarily recognized chemical determinants in the butyrophenone ring (ring 1) and side chain. Inhibition of [3H]haloperidol binding to mAb A by 16 unlabeled haloperidol analogs displayed a good correlation [r = 0.82, n = 16, m = 1.06(+/- 0.38)] with D-2 receptor binding affinity, suggesting that the parts of the D-2 receptor combining site which recognize butyrophenone antagonists may have molecular characteristics which are similar to those of the monoclonal antibody. Other dopaminergic ligands such as dopamine and the D-1 antagonist SCH-23390 were not recognized by monoclonal antibodies raised against the succinic acid conjugate. Monoclonal antibodies raised against the oxime conjugate such as 258(2)-1 (herein referred to as mAb D) primarily recognized chemical determinants in ring 2 and the tertiary amino group of the piperidine ring. Although the D-2 receptor and mAb D both prefer electron-withdrawing substituents in the para position of ring 2, the antibody was more sensitive than the receptor to changes and displayed affinities that were much lower for substituents attached to the p-chlorophenyl ring (ring 2), which were electron donating. In addition, dopamine was able to completely displace 4 nM [3H]haloperidol from mAb D at a concentration of 6 mM.

Animals↗
PubMed1997

Conformational analysis of peptides corresponding to all the secondary structure elements of protein L B1 domain: secondary structure propensities are not conserved in proteins with the same fold.

The solution conformation of three peptides corresponding to the two beta-hairpins and the alpha-helix of the protein L B1 domain have been analyzed by circular dichroism (CD) and nuclear magnetic resonance spectroscopy (NMR). In aqueous solution, the three peptides show low populations of native and non-native locally folded structures, but no well-defined hairpin or helix structures are formed. In 30% aqueous trifluoroethanol (TFE), the peptide corresponding to the alpha-helix adopts a high populated helical conformation three residues longer than in the protein. The hairpin peptides aggregate in TFE, and no significant conformational change occurs in the NMR observable fraction of molecules. These results indicate that the helical peptide has a significant intrinsic tendency to adopt its native structure and that the hairpin sequences seem to be selected as non-helical. This suggests that these sequences favor the structure finally attained in the protein, but the contribution of the local interactions alone is not enough to drive the formation of a detectable population of native secondary structures. This pattern of secondary structure tendencies is different to those observed in two structurally related proteins: ubiquitin and the protein G B1 domain. The only common feature is a certain propensity of the helical segments to form the native structure. These results indicate that for a protein to fold, there is no need for large native-like secondary structure propensities, although a minimum tendency to avoid non-native structures and to favor native ones could be required.

Amino Acid Sequence↗
PubMed1997

Chain conformational analysis of beijeran by n-h map calculations.

Possible regular helix models of beijeran, a new acidic heteropolysaccharide consisting of a trisaccharide as a repeating unit, were investigated. Conformational analyses of the three component disaccharides were first carried out by calculating their relaxed-residue energy maps with respect to the glycosidic bond rotations, phi and psi. A search for possible beijeran chain conformations was carried out by calculating the two-dimensional map of the helix parameters; n (the number of asymmetric units per a fiber repeat) and h (the axial rise per the unit), on the basis of the phi-psi conformations taken from the low energy regions of each of the three energy maps. The n-h values of the helix models with low steric energies were mostly found to be around the experimental values (n = 2 and h = 1.20-1.25 nm), which may support the present methodology. It was also suggested that the internal flexibility of beijeran chain allowed it to conform in diverse helical structures, each of which were reasonably in accord with the observed n-h values. The three representative helix models were finally proposed for the beijeran chain conformation in the crystal structure.

Azotobacter↗
PubMedDate not supplied

Quantum pharmacologic studies applicable to the design of anticonvulsants: theoretical conformational analysis and structure-activity studies of barbiturates.

We report the first large-scale systematic quantitative structure-activity relationship (QSAR) study of barbiturates, correlating molecular structures with anticonvulsant activity. To achieve this QSAR study, we devised a four-step strategy. In step 1, an optimal quantum mechanical technique for determining the geometry and shape (conformation) of barbiturates was ascertained; this is the AM1 semiempirical molecular orbital method. In step 2, the AM1 method was used to optimize the structures and molecular properties of 48 barbiturates with varying anticonvulsant activity. In step 3, discriminant analysis and regression analysis statistical calculations were used to correlate the molecular properties of the 48 analogues against maximal electroshock (MES) and subcutaneous metrazol (s.c.Met)-induced seizures. In step 4, the contribution of molecular electrostatic properties to barbiturate anticonvulsant activity was further refined by quantum mechanical derived molecular electrostatic potential (MEP) maps. Using this four-step strategy, we defined the pharmacophore, the portion of a molecule responsible for bioactivity, for anti-MES and anti-s.c.Met activity. For anti-s.c.Met activity, barbiturate lipophilicity and geometry are important considerations; for anti-MES activity, barbiturate topologic and electronic properties have increased relevance.

Anticonvulsants↗
PubMed1986

Conformational analysis of the octamer d(G-G-C-C-G-G-C-C) in aqueous solution. A one-dimensional and two-dimensional proton NMR study at 300 MHz and 500 MHz.

Proton NMR studies in H2O and 2H2O were carried out on the self-complementary DNA octamer d(G-G-C-C-G-G-C-C) and compared with similar studies on the dimethylated analogue d(G-G-m5C-m5C-G-G-C-C) [Sanderson, M. R., Mellema, J.-R., van der Marel, G. A., Wille, G., van Boom, J. H. & Altona, C. (1983) Nucleic Acids Res. 11, 3333-3346]. Base, H1', H2' and H2" resonances were assigned by means of two-dimensional nuclear Overhauser spectroscopy (NOESY) and correlated spectroscopy (COSY) experiments. Chemical shift vs temperature profiles were used to analyze the temperature-dependent conformational behaviour and to extract thermodynamic parameters for the duplex-to-coil transition. Analysis of proton-proton couplings were used to discriminate between J1'2' and J1'2" and between the H2' and H2" resonances as well as to obtain conformational parameters of the sugar rings. From the NOESY and COSY experiments, the temperature profiles and the analysis of the coupling data it is concluded that: (a) the compound adopts a B-DNA-type helix in solution; (b) the sugar rings in the intact duplex display limited conformational freedom; (c) methylation of the cytosine bases at the C5 position has no measurable effect on the conformational behaviour of the octamer, nor on the conformation of the sugar rings; however, methylation does increase the stability of the duplex in aqueous solution under conditions of low salt concentration.

Carbohydrate Conformation↗
PubMed2001

Ether phospholipid-AZT conjugates possessing anti-HIV and antitumor cell activity. Synthesis, conformational analysis, and study of their thermal effects on membrane bilayers.

The 1-O-hexadecyl-2-O-methyl-sn-glyceryl phosphodiester AZT 4 and hexadecyl-phosphodiester AZT 5 derivatives were synthesized and found to be active against HIV-1, HIV-2, and tumor cell proliferation. Compared to AZT, compound 4 possessed ca. 10-fold lower anti-HIV activity and ca. 10-fold higher anti-tumor cell activity. Compound 5 was 10-fold less potent than compound 4 in both biological tests. In an attempt to correlate biological activity of compounds 4 and 5 with structure, their conformational and thermal effects on membrane bilayers were compared using a combination of NMR spectroscopy, computational analysis, and Differential Scanning Calorimetry. The obtained results showed that compound 4 adopts a compact conformation in which the alkyl chain, the 2-methoxyglyceryl functionality, and the methyl group of thymine are in spatial proximity, while analogue 5 possesses a less compact conformation of the nucleoside base and the alkyl chain. The presence of the 2-methoxyglyceryl group in compound 4 may augment its potency by inducing a turn of the alkyl chain stabilized by hydrophobic interactions. The DSC scans show that conjugate 4 affects less effectively the thermotropic properties of model membrane bilayers than compound 5. This may be attributed to the fact that compound 4 is incorporated in a compact conformation and does not perturb significantly the trans:gauche isomerization of the membrane phospholipids. In contrast, conjugate 5 may enter with a less compact conformation and perturb more the membrane bilayers.

Animals↗