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At least 217 records · Page 12Linked to original sources
PubMed1988

Conformational analysis and structural comparisons of (1R,3S)-(+)- and (1S,3R)-(-)-tefludazine, (S)-(+)- and (R)-(-)-octoclothepin, and (+)-dexclamol in relation to dopamine receptor antagonism and amine-uptake inhibition.

Conformational analysis with molecular mechanics (MM2(85] and molecular superimposition studies of (1R,3S)-(+)- and (1S,3R)-(-)-4-[3-(4-fluorophenyl)-6-(trifluoromethyl)indan-1-yl]-1- piperazineethanol (tefludazine) and (S)-(+)- and (R)-(-)-octoclothepin have been employed to identify biologically active conformations of these compounds with respect to dopamine receptor antagonism and amine-uptake inhibition. In contrast to what is commonly assumed, these studies indicate that the conformation of (S)-(+)-octoclothepin responsible for the dopamine receptor antagonism is different from the one observed in the crystal. From least-squares molecular superimpositions with the potent and stereoselective dopamine receptor antagonist (1R,3S)-tefludazine, biologically active conformations for the two compounds on the dopamine receptor have been deduced. This analysis also rationalizes the enantioselectivity of octoclothepin on the dopamine receptor. The X-ray structure of (S)-(+)-octoclothepin is shown to correspond structurally to the 1S,3R enantiomer of tefludazine, which is an amine-uptake inhibitor. This correspondence provides a structural basis for the norepinephrine (NE) uptake blocking properties of octoclothepin. It is predicted that the enantioselectivity of the NE-uptake inhibition of octoclothepin should be low with the S-(+) enantiomer as the more active optical isomer. A comparison of the deduced biologically active conformation of (S)-(+)-octoclothepin with (+)-dexclamol is also discussed on the basis of earlier derived superimposition studies with (+)-dexclamol.

Antipsychotic Agents↗
PubMed2003

Application of NMR, molecular simulation, and hydrodynamics to conformational analysis of trisaccharides.

The preferred conformations and conformational flexibilities of the trisaccharides alpha-D-Glcp-(1-->2)-beta-D-Glcp-(1-->3)-alpha-D-Glcp-OMe (I) and alpha-D-Glcp-(1-->3)[beta-D-Glcp-(1-->4)]-alpha-D-Glcp-OMe (II) in aqueous solution were determined using nuclear magnetic resonance (NMR) spectroscopy, molecular dynamics (MD) and Langevin dynamics (LD) simulations, and hydrodynamics calculations. Both trisaccharides have a vicinal substitution pattern in which long range (nonsequential) interactions may play an important role. LD simulation at 600 K indicated that the all-syn conformation predominated, though other conformations were apparent. NOE data and MD and LD simulations at 298 K all indicated that trisaccharide I is a single all-syn conformer in solution. Given that previous studies showed evidence of anti-conformers in beta-D-Glcp-(1-->2)-beta-D-Glcp-(1-->3)-alpha-D-Glcp-OMe, this result provides an example of how changing the anomeric configuration of one residue from beta to alpha can make an oligosaccharide more rigid. Discrepancies in inter-ring distances obtained by experiment and by simulation of the all-syn conformer suggest the presence of an anti-psi conformation at the beta-(1-->4)-linkage for II. A combined analysis of measured and calculated translational diffusion constants and (13)C T(1) relaxation times yield order parameters of 0.9 for each trisaccharide. This implies that any interconversion among conformations is significantly slower than tumbling. Anisotropies of approximately 1.6 and 1.3 calculated for I and II, respectively, are consistent with the observed relatively flat T(1) profiles because the tumbling is not in the motional narrowing regime.

Carbohydrate Conformation↗
PubMed1997

Conformational analysis using distance geometry methods.

Distance geometry methods have been used extensively to build models of molecules of various sizes, including small molecules, peptides, and proteins. These methods are often overlooked as tools for conformational analysis, even though they often perform as well as other conformational sampling methods. We have implemented two new distance geometry approaches in the DGEOM95 package. In the first new method, the traditional embedding algorithm is replaced with a procedure that generates random 4D coordinates for each atom, followed by refinement of these coordinates into 3D using the distance geometry error function. The conformational sampling produced by this method is comparable to that obtained with partial metrization, and superior to that obtained with the original embedding procedure. In the second method, a molecular dynamics step is included in the refinement stage. Although this method can be applied to any embedding algorithm, substantial improvements in sampling are seen primarily with the original embedding algorithm.

Algorithms↗
PubMed2003

The utility of infrared spectroscopy for quantitative conformational analysis at a single temperature.

The carbonyl stretching vibration of 2-bromocyclohexanone (1) has been measured in a variety of solvents. It is shown that its component intensities are not only dependent on the populations of the axial and equatorial conformers, but are also dependent on the molar absorptivities (epsilon ) which are specific for each conformer in each solvent. In CCl(4), the axial and equatorial conformers have epsilon values of 417 and 818 l mol(-1) x cm(-1), respectively, while in CH(3)CN solution, the values were 664 and 293 l mol(-1) x cm(-1). These results are supported by results of theoretical calculations of frequencies, which gave an intensity of 223.8 kM mol(-1) x(1782 cm(-1)) for the axial and 174.4 kM mol(-1) x (1802 cm(-1)) for the equatorial conformer, indicating that the axial conformer presents a larger molar absorptivity than the equatorial one in the vapor phase. Moreover, the results presented here clearly demonstrate that although infrared spectroscopy at a single temperature can be an important auxiliary technique for conformational analysis, it must not be used to quantify conformational preferences of a molecule if the absorption molar coefficients for each conformer are not known or not amenable to experimental determination.

Carbon↗
PubMed1992

Design, synthesis and conformational analysis of gamma-turn peptide mimetics of bradykinin.

Gamma-turns are regular secondary structure elements, found with some frequency in small peptides, that have been implicated in the biologically active conformations of several systems. This report describes the design, synthesis and conformational analysis of a non-peptide gamma-turn mimetic. Low energy conformations of the mimetic system exhibit good conformational agreement with an experimentally observed peptide gamma-turn. The mimetics were incorporated into the nonapeptide bradykinin, for which a gamma-turn, formed by residues Ser 6 to Phe 8, has been hypothesized to be a bioactive conformation. The results indicate that a bioactive conformation of bradykinin may include a reverse turn at this position.

Amino Acid Sequence↗
PubMedDate not supplied

Conformational analysis and TDDFT calculations of the chiroptical properties of tris [1,2-propanediolato(2-)-kappaO,kappaO'] selenium/tellurium and related compounds.

The tris(didentate) chelates [E(OCR1R2CR3R4O)3], with E = Se and Te, display both configurational (delta or lambda; R or S) and conformational (delta or lambda) chirality. In order to assess the contributions of these three chiral arrays to the Cotton effects of the chelates and to elucidate their stereochemistry in the gas phase and in solution, calculations of the UV and CD spectra (down to 180 nm), and also of the relative stability of the chelates, have been performed at the TDDFT/TZVP/B-P86 level. An extensive conformational analysis has supplied additional information on the relevant conformers in the conformational manifold. It was found that the dominant CD effect reflects mostly the delta/lambda twists of the three five-membered ligand rings, and less so the influence of the A/A core configuration, while the contributions of any R/S chiral carbon atoms of the ligand rings are negligible. The sign, the intensity, and the energy of this dominant CD band are found to depend on the stereochemistry of the chelates in a predictable way. Among the conformers, those with equatorially disposed methyl substituents are much preferred. These results make it possible to determine the absolute configuration (A/A) and conformation (delta/lambda) of the chelates from the CD data.

Journal Article↗
PubMed1999

Methylation-sensitive, single-strand conformation analysis (MS-SSCA): A rapid method to screen for and analyze methylation.

We have developed methylation-sensitive, single-strand conformation analysis (MS-SSCA) as a method of screening for methylation changes. Bisulfite modification converts cytosines to thymines, but methylated cytosines remain unchanged. This modification creates sequence differences between methylated and unmethylated samples, which can be resolved by SSCA. SSCA is 70-95% efficient at detecting single base changes in a fragment. As bisulfite modification of methylated DNA would typically involve several base changes in a fragment, the efficiency of detecting methylation using MS-SSCA could approach 100%. We applied this method to analyze the BRCA1 promoter CpG island in breast cancer samples. About 20% of sporadic breast cancers are hypermethylated at the BRCA1 promoter CpG island. MS-SSCA rapidly detected those tumors that had previously been shown to be methylated by Southern blotting. The variant bands detected by SSCA were analyzed by sequencing and shown to be methylated. MS-SSCA is a simple method for screening large numbers of samples for methylation and can accelerate genomic sequencing, as all bands can be isolated and sequenced directly.

BRCA1 Protein↗
PubMed1997

Role of a nonnative interaction in the folding of the protein G B1 domain as inferred from the conformational analysis of the alpha-helix fragment.

BACKGROUND: The role of local interactions in protein folding and stability can be investigated by the conformational analysis of protein fragments. The hydrophobic staple and Schellman motifs have been described at the N and C terminus, respectively, of protein alpha-helices. These motifs are characterized by an interaction between two hydrophobic residues, one outside the helix and one within the helix, and their importance for helix stability has been analyzed in model peptides. In the alpha-helix of the protein G B1 domain, only the Schellman motif is formed--the hydrophobic staple motif is absent despite the favourable sequence pattern. We have experimentally analyzed the solution conformation of the 19-41 fragment of protein G. This peptide comprises the helical residues and contains both the hydrophobic staple and Schellman motif sequences. RESULTS: In the isolated peptide in water, the hydrophobic staple motif is formed and stabilizes the helical structure as compared with a shorter peptide lacking it, but the Schellman motif is not formed. In 30% aqueous TFE, the helix is more stable than in pure water and both motifs are formed. CONCLUSIONS: The results suggest that the importance of each motif for the folding and stability of protein G is different. The nonnative hydrophobic staple interaction can help to nucleate the helix at the beginning of folding but has later to be disrupted. The Schellman motif, while not providing enough energy for substantial helix stabilization in the unfolded state, could be important for determining the local fold of the sequence in the context of the rest of the protein.

Amino Acid Sequence↗
PubMed1990

Four-stranded DNA helices: conformational analysis of regular poly(dT).poly(dA).poly(dA).poly(dT) helices with various types of base binding.

The paper presents results obtained in conformational analysis of homopolymeric four-stranded poly(dT).poly(dA).poly(dA).poly(dT) DNA helices in which the pairs of strands with identical bases are parallel and have a two-fold symmetry axis. All possible models of base binding to yield a symmetric complex have been considered. The dihedral angles of sugar-phosphate backbones and helix parameters, which are consistent with the minima of conformational energy for four-stranded DNAs, have been determined using the results of optimization of conformational energy calculated at atom-atom approximation. Potential energy is shown to depend on the structure of base complexes and on the mutual orientation of unlike strands. Possible biological functions of four-stranded helices are discussed.

Base Composition↗
PubMed1984

Conformational analysis of suloctidil and derivatives inserted in lipid layers.

Interaction between suloctidil (CP 556 S) and lipids (phosphatidylcholine, phosphatidylserine) is studied using a new conformational analysis procedure. This analysis is extended to two compounds related to suloctidil but bearing no protonable group (CP 894 S) or of different hydrophobicity (CP 1136 S). It gives a molecular description of the mode of insertion of the drugs into the lipid layer. The influence of the calculated lipid-drug interaction and area occupied per drug molecule in the lipid layer is tentatively related to the effect on the lipid dynamics. For a given conformer, an effect on the lipid dynamics is expected only if (a) the area occupied per conformer is similar to that of the lipid and/or (b) the drug-lipid interaction energy is equal or superior to that of the lipid-lipid interaction. These predictions are analyzed in terms of the available experimental data.

Lipids↗
PubMed2000

Reference strand mediated conformation analysis resolves HLA-DRB1 typing ambiguities when matching for unrelated bone marrow transplantation.

We show here the use of reference strand mediated conformation analysis (RSCA) to unambiguously resolve the HLA-DRB1 typing of two individuals which were selected as potential unrelated donors for bone marrow transplantation (BMT). In the first case, both sequence-specific primer (SSP) amplification and sequence-specific oligonucleotide probing (SSO), routinely used in different tissue typing laboratories gave, for the two unrelated donors, the same ambiguous typing of HLA-DRB1*04011+*0403 or DRB1*0407+*0413. In this case sequence-based typing (SBT) was not the method of choice to resolve the situation, due to the sequence ambiguities of these two given combinations. RSCA of both samples, using homozygous typing cells (HTCs) for DRB1*04011, *0403 and *0407 as internal controls, gave the unambiguous result that both donors were HLA-DRB1*04011+*0403. In the second case, a donor was typed as DRB1*1102+1103 by SSP, while SSO excluded the DRB1*1102 allele. The patient was unambiguously typed as DRB1*1101+1103 by both techniques. RSCA, using DNA from reference cell lines as internal controls, gave the unambiguous typing that the donor was DRB1*1103 homozygous.

Alleles↗
PubMed1995

Conformational analysis of methylphenidate and its structural relationship to other dopamine reuptake blockers such as CFT.

PURPOSE: This work was performed 1) to determine the conformational preferences of the threo and erythro isomers of the dopamine reuptake blocker methylphenidate, 2) to determine the crystal conformation of the threo isomer, 3) to confirm the absolute configuration of the more active threo enantiomer, and 4) to incorporate the compound into a previously determined pharmacophore for dopamine reuptake blockers. METHODS: A conformational analysis was performed with the MM2-87 program, a crystal of the (-)-threo HCl salt was analyzed by x-ray crystallography, and the global minima of the (+)-threo isomer and the potent dopamine reuptake blocker CFT were superimposed. RESULTS: In the global minimum of the threo isomer, the carbonyl oxygen of the ester group is oriented toward the ammonium group as was also found in the crystal state. In the erythro isomer, the ester group prefers an extended conformation relative to the piperidine group. The absolute configuration of the biologically active (+)-threo enantiomer was confirmed to be R,R. The atomic sequence from the amine group through the ester group is identical in the active enantiomers of methylphenidate and CFT. CONCLUSIONS: The dopamine reuptake protein requires a precise orientation of the ammonium and ester groups but allows considerable leeway in the position of the phenyl ring. The pKa of the threo isomer is predicted to be higher than that of the erythro isomer.

Cocaine↗
PubMed1995

The use of the AMBER force field in conformational analysis of carbohydrate molecules: determination of the solution conformation of methyl alpha-lactoside by NMR spectroscopy, assisted by molecular mechanics and dynamics calculations.

The solution conformation of methyl alpha-lactoside has been studied through nmr spectroscopy and molecular mechanics calculations using the assisted model building with energy refinement (AMBER) force field. The nmr data have included nuclear Overhauser effect (NOE) measurements both in the laboratory and rotating frames, longitudinal relaxation times, and homonuclear and heteronuclear coupling constants. The steady-state and transient NOEs have been interpreted in terms of an ensemble average distribution of conformers, making use of the complete relaxation matrix approach. The molecular mechanics calculations have been performed at two dielectric constants [epsilon = 1*r and 80 Debyes (D)] in an exhaustive way, and have been complemented with specific calculations at intermediate epsilon values. Relaxed energy maps and adiabatic surfaces have been generated for the different dielectric constants. The probability distribution of conformers has been estimated from these steric energy maps. Molecular dynamics simulations in vacuo have also been performed. The experimental results indicate that the beta (1-->4)-glycosidic linkage shows some fluctuations among three low energy regions, although spends ca. 85% of its time in the region close to the global minimum. It is shown that the overestimation of the electrostatic contributions in AMBER is responsible for the failure of this force field to explain the experimental results when used at low dielectric constant (epsilon < 20 D). The matching between the expected and observed facts increases for epsilon > 40 D. Different conditions have been tested to perform temperature constant molecular dynamics simulations in vacuo, which have indicated that, when used without explicit solvent, this force field should only be employed in a qualitatively way when analyzing dynamical properties of oligosaccharides.

Carbohydrate Conformation↗
PubMed1999

HLA-A typing by reference strand-mediated conformation analysis (RSCA) using a capillary-based semi-automated genetic analyser.

HLA typing of class I loci by reference strand-mediated conformation analysis (RSCA) using a slab gel genetic analyser has been described. This study adapted the method for use in the capillary based ABI PRISM 310. Control DNA samples were used to create a database of mobility values for 37 HLA-A alleles. The technique was validated by comparing RSCA and sequence-specific oligonucleotide probe (SSOP)/sequence-specific primer amplification (SSP) HLA-A locus typing results from 214 cord blood samples. Of the samples tested, 6.5% required confirmatory typing by SSP, compared with a repeat rate of 10-40% for SSOP. In 200 samples where no SSP was necessary, there was 100% concordance between RSCA and previous results. The ABI PRISM 310 RSCA method defines HLA-A types at medium resolution and is quick and easy to implement.

Electrophoresis, Capillary↗
PubMed1995

Conformational analysis of 19-oxygenated steroids with a 4-ene or 2,4-diene structure, potential intermediates of aromatase reaction, with semiempirical molecular orbital PM3 calculations.

Conformational analysis of potent competitive inhibitors of aromatase, androst-4-enes 5, as well as 2,4-diene steroids 3, 4, and 6 was carried out, using theoretical calculations, to determine the stereochemistry of their aromatase-catalyzed oxygenation. In the steroids examined, both the 19-alcohols and the 19-aldehydes favor the above- A ring conformation among the possible three in each. The results suggest that the 3-deoxy steroid 5a as well as the 2,4-diene steroids 4a and 6a would be oxygenated at C-19 by aromatase through the same stereomechanism as that involved in the androstenedione aromatization.

Aromatase↗
PubMed1995

Conformational analysis of segments of oxidized cellulose. Part I: Molecular modelling of glucuronic acid dimers considering the effect of counter-ions and a polar environment.

Conformational analysis of various forms of glucuronic acid dimers as the model structures of oxidized cellulose has been performed using molecular mechanics with a CVFF force field. The effects of ionization of carboxyl groups, ion pairing with explicit consideration of counter-ions (Na+, Mg2+) and the implicit inclusion of a solvent effect via the dielectric constant, epsilon, have been simulated. The non-ionized glucuronic acid dimer shows conformational behaviour similar to that of unoxidized cellobiose. The ionization of COOH groups leads to strong destabilization of C and D conformers (with both COO- groups on the same side of the molecule), while complexation with counter-ions leads to strong stabilization of these forms which yield highly wound low-pitch helices. An increase in the solvent polarity has an attenuating effect on the behaviour described above.

Anions↗
PubMed1999

Synthesis, conformational analysis and antinociceptive activity of 1-[N-methyl-(2-phenylethyl)amino]methyl-1,2,3,4-tetrahydroisoquinoline derivatives.

New derivatives of 1-[N-methyl-(2-phenylethyl)amino]methyl-1,2,3,4-tetrahydroisoquinoline were synthesized. The antinociceptive activity of the compounds, determined by the mouse tail-flick test, showed that the introduction of a hydroxy substituent in position 5 of the isoquinoline nucleus generated compounds 4c and 5c, which were as potent as codeine. Conformational analysis and superimposition of energy minima conformers of the compounds on phenazocine revealed that the main proposed opioid pharmacophores were well matched.

Analgesics↗