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PubMed1988

Computed conformational analysis of lipoxins and their ionic complexes.

The possible molecular conformations of four structurally and biologically different lipoxins derivatives were predicted by a systematic structure tree theoretical analysis. This method takes into account the London-Van der Waals energy of interaction, the electrostatic interaction, the rotation energy of the torsional angles and the energy of transfer through a possible lipid-water interface. Finally, the conformers derived from the structure tree and with a high probability of existence were submitted to the energy minimization procedure. The most probable conformers of lipoxin A: 5S,6R,15S-trihydroxy-7,9,13 trans-11 cis-eicosatetraenoic acid (LXA); 11 trans lipoxin A: 5S,6R,15S-trihydroxy-7,9,11,13 trans-eicosatetraenoic acid (11t-LXA); lipoxin B: 5S,14R 15S-trihydroxy-6,10,12 trans-8 cis-eicosatetraenoic acid (LXB) and 8 trans lipoxin B: 5S,14R,15S-trihydroxy- 6,8,10,12 trans-eicosatetraenoic acid (8t-LXB) in their isolated form or when forming complexes with one calcium ion are presented. The four isolated compounds lead to vastly different conformations. Lipoxin A can form the most globular conformer while lipoxin B seems to be slightly more extended. The all trans isomer of lipoxin B forms an extended conformer and 11 trans lipoxin A gives a fully extended molecule. Complexes of a pair of these compounds with one calcium ion were shown to lead to vastly different conformations. Both (LXA) 2Ca and (LXB)2Ca form crumpled or extended structure, the LXA molecules being more wrapped around Ca2+ than LXB molecules. The (11t-LXA)2Ca and (8t-LXB)2Ca complexes present a high probability of extended conformations. Our description merely shows that the peculiar stereochemistry of these molecules lead to equilibria between conformers or to very static conformers, the flexibility and rigidity of which being probably relevant in view of their different biological activities.

Chemical Phenomena↗
PubMed2007

Structural and conformational analysis of two native procyanidin trimers.

The structure and conformation of two native procyanidin trimers in water have been determined using 2D NMR and molecular mechanics. The results show the existence of four rotameric forms, one of which is predominant (60 to 80%). These four rotamers are shown to be in slow to intermediate exchange on the NMR timescale. Both trimers, whose structures vary owing to a different substitution of one carbon atom, adopt conformations in which stacking between different phenolic rings is favored.

Biflavonoids↗
PubMed1980

Quantum mechanical conformational analysis of heterocyclic analogues of norephedrine.

Studies on the conformation of several structural analogues of norephedrine, thiophene, carbazole and furan, were carried out using the differential PCILO method. The erythro-forms of these compounds possess minima on the conformation map corresponding to a gauche conformation with synclinal H-atoms. This result is in good agreement with the proton-proton coupling constants found in previous NMR-studies. H-NMR-studies suggest for the threo-isomers of the studied molecules an equilibrium between the trans- and gache-conformations of the ethanolamine chain. Present calculations agree fairly well with this result. All the studied molecules possess conformational minima corresponding to the folded form of the side chain believed responsible for the physiological activity of norephedrine. The distances between "N" and 'O' atoms in this preferred conformation correspond to the model proposed by Kier and Pullman for alpha-adrenergic receptors.

Crystallography↗
PubMedDate not supplied

Theoretical and experimental conformational analysis of two diastereomeric "Val"-statine derivatives.

The preferred conformations and self-association modes of the two diastereomeric N-acetyl, methylamides of 3-hydroxy, 4-amino, 5-methylhexanoic acid ("Val"-statine) with (S,S) and (R,S) configurations at the 3-hydroxy and 4-amino carbon atoms, respectively, were determined in solution as well as in the crystal state by infrared absorption, 1H nuclear magnetic resonance and x-ray diffraction. A corollary conformational energy computation study was also carried out. In the crystal state intramolecular H-bonds are absent in both structures. However, the change in chirality of the carbon atom carrying the hydroxy group and the presence of a co-crystallized water molecule in the (S,S) isomer induce partially different backbone and "Val" side chain conformations and divergent intermolecular H-bonding schemes in the two isomers. A marked propensity to self-aggregate is seen in solvents of low polarity. The two isomers, however, are largely solvated in solvents of high polarity. Conformational energy computations indicate that in vacuo both diastereomers exhibit a significant flexibility and the conformers presenting absolute minima are not stabilized by any intramolecular bonding.

Amino Acid Sequence↗
PubMed1985

SMS 201-995, an octapeptide somatostatin analogue. Assignment of the 1H 500 MHZ n.m.r. spectra and conformational analysis of SMS 201-995 in dimethylsulfoxide.

The possible conformations of SMS 201-995, an active analogue of somastostatin, have been studied in dimethylsulfoxide solution by 500 MHz proton n.m.r. spectroscopy. The assignments have been made by use of 2D-correlated methods to detect long-range coupling connectivities in aromatic residues and between the alpha protons of consecutive residues. NOESY experiments enabled us to correlate amide and alpha protons of neighbouring amino acid residues, which indicate a less flexible situation than in water. Measurements of temperature coefficients of the amide protons, of NH-C alpha H coupling constants and NOE effects are in favour of one predominant conformation with a beta turn, of type II', involving amino acids Phe3 to Thr6.

Amino Acid Sequence↗
PubMed1983

[Topography of the active site of the noradrenaline neuronal membrane carrier based on the theoretical conformation analysis of inhibitors of neuronal catecholamine uptake].

All equilibrium conformations for nine ligands, essentially different in structure, of the noradrenaline carrier through the synaptosomal membrane of rat hypothalamus were calculated by semi-empirical method. Among these compounds were amphetamine, methylphenidate, tricyclic antidepressants. The conformational energy minimization was performed in the space of torsional and bond angles. Geometrical characteristics of the conformers were determined in the cartesian coordinate system fixed relative to the benzene ring and nitrogen atom of the ligand. The selection of biologically active (productive) conformations was made according to the following criteria: 1) low conformational energy; 2) similarity of the nitrogen atoms and phenyl rings spatial disposition in all ligands; 3) accessibility for intermolecular interactions of the same sides of functional groupings in all ligands. The above criteria enabled the productive conformations for all ligands to be chosen unambiguously. The productive conformation of noradrenaline was found to have the Ph-C-C-N fragment in perpendicular trans-conformation. A topographic model for the carrier active site was suggested, its components being the nucleophilic and two arylophilic groups situated against the most accessible sides of the functional moieties of the productively bound ligands.

Amphetamine↗
PubMed2004

Geometric algorithms for the conformational analysis of long protein loops.

The efficient filtering of unfeasible conformations would considerably benefit the exploration of the conformational space when searching for minimum energy structures or during molecular simulation. The most important conditions for filtering are the maintenance of molecular chain integrity and the avoidance of steric clashes. These conditions can be seen as geometric constraints on a molecular model. In this article, we discuss how techniques issued from recent research in robotics can be applied to this filtering. Two complementary techniques are presented: one for conformational sampling and another for computing conformational changes satisfying such geometric constraints. The main interest of the proposed techniques is their application to the structural analysis of long protein loops. First experimental results demonstrate the efficacy of the approach for studying the mobility of loop 7 in amylosucrase from Neisseria polysaccharea. The supposed motions of this 17-residue loop would play an important role in the activity of this enzyme.

Algorithms↗
PubMed1993

Conformational analysis of mu-selective [D-Ala2,MePhe4]enkephalins.

The conformational space of the potent mu-selective opioids [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAGO) and [D-Ala2,MePhe4,Met(O)-ol5]enkephalin (FK 33-824) has been analyzed by 1H-NMR spectroscopy and theoretical calculations involving systematic conformational searching and energy minimizations. A cis-trans equilibrium of the Gly3-MePhe4 amide bond is induced by the N-methyl group, and the more energetically favoured trans isomer is proposed as the biologically relevant form. A compact interaction between the side chains of Tyr1 and D-Ala2 was demonstrated by NOE and ROE effects in both peptides in D2O and DMSO-d6, further supported by shielding of the D-Ala2 methyl protons in both solvents. Analysis of coupling constants, NOE and ROE data indicated significant restriction of the conformational freedom of the MePhe4 side-chain for both peptides in the two solvents. The NMR results and theoretical calculations point towards folded low energy conformations characterized by a beta II-type turn around Gly3-MePhe4. For the trans isomer, a Tyr1-MePhe4 phenyl ring separation between 8.5 and 12.5 A was accompanied by proximity between the D-Ala2 side chain and the C-terminal in low energy conformations. The results are in good agreement with available data on related active enkephalins. The conformational effects induced by simultaneous incorporation of D-Ala2 and MePhe4 in enkephalins is discussed in the light of the enhanced mu-opioid receptor selectivity and activity of these peptides.

Amino Acid Sequence↗
PubMed1992

Conformational analysis of a 12-residue analogue of mastoparan and of mastoparan X.

We have investigated the conformational properties of a truncated analogue of mastoparan and of mastoparan X, both peptides from wasp venom. The electrostatically driven Monte Carlo method was used to explore the conformational space of these short peptides. The initial conformations used in this study, mainly random ones, led to alpha-helical conformations. The alpha-helical conformations thus found exhibit an amphipathic character. These results are in accord with experimental data from NMR and CD spectroscopy.

Amino Acid Sequence↗
PubMed1997

Mono- and bicyclic analogs of parathyroid hormone-related protein. 2. Conformational analysis of antagonists by CD, NMR, and distance geometry calculations.

The conformation of the three cyclic antagonist analogs of parathyroid hormone-related protein (PTHrP)-(7-34) [[Lys13,Asp17]PTHrP-(7-34)NH2,[Lys26,Asp30 ]PTHrP-(7-34)NH2,[Lys13,Asp17,Lys26, Asp30]PTHrP-(7-34)NH2] is investigated by CD, NMR, and extensive computer simulations in aqueous solution and a TFE:water mixture. The structural analysis of these peptides, designed to stabilize different regions of the sequence in alpha-helical conformations, is an important step in addressing the correlation between helical content and binding affinity and bioactivity in this hormone-receptor system. Results from CD and NMR spectroscopy of all three analogues in aqueous solution indicate the presence of alpha-helix only in regions containing a 20-membered lactam ring. Upon addition of TFE, the three analogues display differences in the anticipated increase in helical content. The high-resolution structures produced at 50:50 TFE:water indicate specific differences in the extent and location of the helical regions. These conformations provide insight into the biological profiles of these analogues, reported in the previous manuscript [Bisello et al. (1997) Biochemistry 36, 3293-3299]. Since all three analogues are alpha-helical in the C-terminal region (residues 25-34 have been previously identified as containing the binding domain) and display similar binding affinities, we conclude that this conformational feature is important for the interaction between the peptide and the receptor. The extent of the helix (toward the N-terminus) and the presence of a hinge in the central region of the peptide play roles in the observed efficacy as measured by antagonism of PTH-stimulated adenylyl cyclase activity. The most active analogue consists of helical segments from residues 13-18 and 20-34, separated by a kink centered at Arg19.

Amino Acid Sequence↗
PubMed2006

Conformational analysis of nine-membered cyclic acetals. Stereoelectronic effect in 2,4- and 3,5-benzodioxonine derivatives.

Conformations of the title compounds were examined using DFT calculations and NBO analysis in order to find the origins of their conformational preferences. The most stable conformations were TBC and TCBtype-1 for the 2,4- and 3,5-benzodioxonine derivatives, respectively. In both of these conformations the acetal moiety adopts the g+/-g+/- geometry. The NBO analysis yielded values of the stabilization energy associated with the stereoelectronic nO --> sigmaC-O* interactions that were highest for conformations other than the global minima. Conformers displaying the strongest interactions followed different patterns of atom arrangement within the acetal moiety, namely g+g-, and those in which one or both of the torsion angles within the C-O-C-O-C segment were close to 90 degrees . Steric repulsion caused by alkyl substituents at the anomeric carbon was found to influence the strength of the nO --> sigmaC-O* stabilization through modification of bond lengths and torsion angles. The adopted ground-state conformations result from accommodation of steric repulsions and stabilizing stereoelectronic interactions. It was shown that DFT calculations of conformational preferences of acetals together with GIAO prediction of 13C chemical shifts should be a useful methodology for studies on conformation and conformational equilibria of acetals in solution.

Journal Article↗
PubMed1999

Protein loops on structurally similar scaffolds: database and conformational analysis.

A general problem in comparative modeling and protein design is the conformational evaluation of loops with a certain sequence in specific environmental protein frameworks. Loops of different sequences and structures on similar scaffolds are common in the Protein Data Bank (PDB). In order to explore both structural and sequential diversity of them, a data base of loops connecting similar secondary structure fragments is constructed by searching the data base of families of structurally similar proteins and PDB. A total of 84 loop families having 2-13 residues are found among the well-determined structures of resolution better than 2.5 A. Eight alpha-alpha, 20 alpha-beta, 19 beta-alpha, and 37 beta-beta families are identified. Every family contains more than 5 loop motifs. In each family, no loops share same sequence and all the frameworks are well superimposed. Forty-three new loop classes are distinguished in the data base. The structural variability of loops in homologous proteins are examined and shown in 44 families. Motif families are characterized with geometric parameters and sequence patterns. The conformations of loops in each family are clustered into subfamilies using average linkage cluster analysis method. Information such as geometric properties, sequence profile, sequential and structural variability in loop, structural alignment parameters, sequence similarities, and clustering results are provided. Correlations between the conformation of loops and loop sequence, motif sequence, and global sequence of PDB chain are examined in order to find how loop structures depend on their sequences and how they are affected by the local and global environment. Strong correlations (R > 0.75) are only found in 24 families. The best R value is 0.98. The data base is available through the Internet.

Amino Acid Sequence↗
PubMed2003

Capillary electrophoresis-based single strand DNA conformation analysis in high-throughput mutation screening.

The generation of the draft human genome sequence has created new possibilities for diagnosis, prevention, and treatment of human disease. One consequence of these new possibilities is an increasing need for methods and technology that can be used for high-throughput screening for mutations in large DNA sample materials. In recent years, a number of mutation screening methods have emerged that are based on the analysis of sequence-dependent changes in the conformation of single- and double-stranded DNA using capillary electrophoresis. Common features of these methods are high sensitivity and reproducibility as well as the possibility for automation and massive parallelization. Thus, at present they are among the most attractive technologies for high-throughput mutation screening. This review describes the recent advances in capillary electrophoresis-based single strand conformation polymorphism (CE-SSCP) for detection of unknown mutations, and assesses its practical usability for high-throughput mutation screening based on the available literature. In addition, future prospects are outlined in light of the recent advances in microchip-based capillary electrophoresis.

DNA Mutational Analysis↗
PubMed1987

Reconstruction of NOESY maps. A requirement for a reliable conformational analysis of biomolecules using 2D NMR.

The modelling of the conformation of a biomolecule in solution is based mainly on the internuclear distances deduced from measurements of nuclear Overhauser effects (nOe) in NOESY correlation maps. The distances are then used as restraints in the energy minimization procedure, which leads to one or several optimized conformations. A general and safe technique for validating these structures with respect to the experimental data is here proposed: from the internuclear distances, the relaxation matrix can be computed under the assumption of a unique rotational correlation time. By stepwise integration of these relaxation equations, the NOESY maps can be accurately reconstructed for any mixing time. Because multi-spin effects are correctly taken into account, any difference between the experimental and theoretical maps can be easily interpreted in terms of conformation, and possible inconsistencies due to conformational averaging can be pointed out. The technique is illustrated for a bacterial lipopeptide, mycosubtilin, the spectrum of which is completely assigned.

Biopolymers↗
PubMed2006

Diazocinones: synthesis and conformational analysis.

1,2,4,5-Tetrazines (prepared from aryl nitriles) condense with isoxazolylcyclobutanones (prepared from 3-benzenesulfonyl-3-vinylcyclobutanol) in methanolic KOH to give conformationally restricted 6-isoxazol-5-yl-6,7-dihydro-5H-[1,2]diazocin-4-ones. The solution 1H NMR spectra of dihydrodiazocinone 1a with phenyl moieties at C3 and C8 reveal two conformations of the eight-membered heterocycle that are non-interconverting on the NMR time scale at ambient temperature. The kinetics of the conversion process, followed by 1H NMR between 21 and 70 degrees C in DMSO solution, yield an activation energy of approximately 21 kcal/mol relative to the kinetic conformer and show an equilibrated ratio of approximately 5:1 of the thermodynamic to the kinetic conformers. The electronic structure calculations on a model dihydrodiazocinone predict geometries for the two conformations. One of these geometries agrees with the X-ray crystallographic analysis of the thermodynamic conformation of 1a.

Azocines↗
PubMed1977

Enkephalin: conformational analysis by means of empirical energy calculations.

Low-energy conformations of methionine-enkephalin were generated by means of an empirical method of computation. Many compact conformations, including those containing various standard bends, were of comparable energy. However, one conformation was found to have a potential energy about 5 kcal/mol (21 X 10(3) J/mol) below that of the large group of compact conformations. In this conformation, the 3-glycyl and 4-phenylalanyl residues form a bend of type II'. The conformation is stabilized by a hydrogen bond between the OH group of the 1-tyrosine side chain and the C==O group of 3-glycine or 4-phenylalanine. The phenylalanine and methionine side chains are relatively unrestricted. The conformation is consistent with published nuclear magnetic resonance parameters--coupling constants, temperature dependence of the chemical shift, and spin-lattice relaxation times. It is likely that the molecule undergoes a conformational change when it is bound to the receptor. Leucine-enkephalin appears to have the same conformation as its methionine homolog.

Calorimetry↗
PubMed1992

Conformational analysis of receptor selective tachykinin analogs: senktide and septide.

The conformational behavior in solution of two receptor selective tachykinin agonists, senktide (succinyl-D-F-MeF-G-L-M-NH2) and septide (pQ-F-F-P-L-M-NH2) is described. Two dimensional cross relaxation NMR spectroscopy is used together with coupling constant data to obtain interproton distance constraints. These results are used in conjunction with semi-empirical energy computations to indicate favorable conformations. Senktide is found to have a high degree of conformational order which is attributed to rotational restriction associated with the N-methylation of phenylalanine. The lowest energy conformation in accord with the experimental interproton distances contains a beta-turn. Interproton distances indicate that septide exists as a random coil or in an extended chain conformation. Energy computations suggest that septide is primarily an extended chain with internal reorientation restricted by the proline residue. These results may be related to the selectivity of these peptides for different receptors, in that the analogs, with conformations more stable than tachykinins, are more receptor selective.

Amino Acid Sequence↗
PubMed1995

Conformational analysis of the calcium complexes formed by meglitinide analogs.

The conformation of calcium complexes formed with meglitinide and its hypoglycemic analogs KAD-1229, A-4166, S 3075 and repaglinide was analyzed by a semi-empirical procedure, which includes calculation of the molecular hydrophobicity potential. The calcium complexes formed with KAD-1229, A-4166, repaglinide or its enantiomer, displayed favourable attributes to act as ionophores. Such was not the case for the poorly efficient insulinotropic agent meglitinide and the biologically inactive enantiomer of A-4166. The configuration of the calcium complex formed with S 3075 also failed to display the features required for a high ionophoretic capacity.

Benzamides↗