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PubMed2004

3D-QSAR analysis of conformationally constrained diacylglycerol (DAG) analogues as potent protein kinase C (PK-C) ligands.

A study of the quantitative structure activity relationships (QSARs) was performed based on the binding affinity (pKi) values of 32 protein kinase C (PK-C) ligands. The QSAR study was carried out by using both three-dimensional descriptors (the steric and electrostatic CoMFA fields) and the physicochemical properties (logP values). The CoMFA analysis provided a reasonable QSAR model, with a cross-validated q2 value of 0.671 and a conventional r2 value of 0.956, which was confirmed by the satisfactory prediction of the experimental binding affinity (pKi) values for a series of 3-alkylidene-5,5-disubstituted tetrahydro-2-furanones included in the test set. The resultant QSAR model will be useful for designing highly potent and selective PK-C ligands.

Diglycerides↗
PubMed1988

Analysis of conformational parameters in nucleic acid fragments. III. Very short chain oligonucleotides. The effect of base stacking.

Studies have been made of conformational parameters in single crystal structures of very short chain oligonucleotides consisting of strands with lengths in the range 2-3 bases. Using published data extracted from the Cambridge structural database for 20 such structures, a total of 14 base-pairs were found, of which 10 were hetero-pairs and 4 homo-pairs. Subjecting these to analysis to examine hydrogen bond parameters, propeller twist, buckle and C1'-C1' separation revealed an average propeller twist of 11.6 degrees, with no dependence of this parameter on hydrogen bonding details. In addition, an analysis of base stacking showed there to be no correlation between in-plane geometry and degree of inter-plane overlap.

Base Composition↗
PubMed1982

High-resolution proton nuclear magnetic resonance analysis of conformational properties of biosynthetic actinomycin analogues.

High-resolution proton nuclear magnetic resonance (1H NMR) has been used to study the conformation and dynamics of biosynthetic analogues of actinomycin D that have been substituted at one or both of the 3'-amino acids with azetidine-2-carboxylic acid, pipecolic acid, or 4-ketoproline for one or both of the prolines. The results of measurements made in organic solvents indicate that the amino acid residues on the alpha and beta pentapeptide lactone rings experience different magnetic environments in all the analogues studied. Analysis of the J alpha NH coupling constants and temperature coefficients for the valine and threonine amide protons indicates that substitution at the 3' position has little effect on the conformational and hydrogen-bonding properties of the amino acids at the 1' or 2' position. Examination of the low-field position of the H alpha proton of the 3'-amino acid reveals that the biosynthetic substitutions were made at a unique site on either the alpha or the beta pentapeptide ring and that only one conformation of proline, azetidine-2-carboxylic acid, or pipecolic acid is observed. In D2O, the dynamics of the prolines appear to differ; one remains in a preferred conformation while the other fluctuates at a rate that is intermediate on the NMR time scale. A possible relationship between the conformational and dynamic properties and the DNA binding and kinetic properties is discussed.

Dactinomycin↗
PubMed1990

Molecular conformational space analysis using computer graphics: going beyond FRODO.

The molecular graphics program FRODO has been modified to support analytical animation of molecular dynamics trajectories. The enhanced program, mdFRODO, supports all features available in FRODO and is interfaced to GROMOS. A variety of analytical animation modes is included. Extensive coloring and atom selection features are implemented to aid the user in distinguishing features of interest in a set of conformations. Molecular conformational space can be analyzed efficiently and comprehended. Animations may be viewed in stereo, and the animated object can be overlaid with any of the standard FRODO objects. The mdFRODO program is of wide use in molecular dynamics, X-ray crystallography and two-dimensional NMR work. Examples illustrating various aspects of collective motion in protein molecules are given and discussed.

Computer Graphics↗
PubMedDate not supplied

A conformational comparison of two stereoisomeric cyclic dermorphin analogues employing NMR and computer simulations.

In a continuation of our program to study the structure-activity relationship of peptide opiates, we report the conformational analysis of two cyclic tetrapeptides related to dermorphin--Tyr-c[D-Orn-Phe-Asp]-NH2 and Tyr-c[D-Asp-Phe-Orn]-NH2. These analogues have similar binding properties marked by a high selectivity for the mu-opioid receptors because of a drastic decrease in the affinity for the delta-opioid receptor. The conformational preferences of these analogues of dermorphin determined from proton nmr, molecular dynamics, and energy minimizations are quite similar. The constraint of the 13-membered ring formed from cyclization is quite evident from the conformational analysis. The constrained ring system acts as a template maintaining the relative orientation of the exocyclic tyrosine and side chain of phenylalanine. Two intramolecular hydrogen bonds measured for the D-Orn analogue in DMSO were disrupted upon the addition of water. For the D-Asp analogue, two intramolecular hydrogen bonds were found stable in DMSO and water. The global conformations of the two peptides determined from nuclear Overhauser effects did not change with the solvent titration. The difference in the hydrogen bonding within the 13-membered ring may account for the slight differences observed in the efficacy of the analogues at the mu-opioid receptors.

Amino Acid Sequence↗
PubMed1980

Modification of cytidines in a Q beta replicase template: analysis of conformation and localization of lethal nucleotide substitutions.

The solution conformation of MDV-1( + ) RNA, a small RNA template replicated autocatalytically in vitro by Q beta replicase, was investigated with sodium bisulfite, a reagent that selectively converts single-stranded cytidines to uridines. The reactivity of 45 of the 76 cytidines in MDV-1( + ) RNA was determined by nucleotide sequence analysis. Only 14 of these 45 cytidines were converted to uridine. Treatment of the RNA with methoxyamine, another single-strand-specific cytidine modification reagent, gave results in good agreement with the bisulfite data. The limited reactivity of MDV-1 ( + ) RNA with these reagents indicates that it is a highly structured molecule. A secondary structure consistent with the chemical modification data is proposed. Modification of MDV-1 ( + ) RNA by bisulfite renders it inactive as a template for RNA replication. This inactivation and the modification of the cytidines at the 3' end of the molecule occur at very similar rates. By using a short complementary RNA "mask" to protect just these cytidines, we demonstrated that the loss of activity resulted from their modification. This implies that one or more of the cytidines in the 3'-terminal sequence is required for template activity and that changes within this sequence can have lethal consequences. The effects of modification elsewhere in the sequence are discussed.

Base Sequence↗
PubMed1998

New developments of the electrostatically driven Monte Carlo method: test on the membrane-bound portion of melittin.

The electrostatically driven Monte Carlo (EDMC) method has been greatly improved by adding a series of new features, including a procedure for cluster analysis of the accepted conformations. This information is used to guide the search for the global energy minimum. Alternative procedures for generating perturbed conformations to sample the conformational space were also included. These procedures enhance the efficiency of the method by generating a larger number of low-energy conformations. The improved EDMC method has been used to explore the conformational space of a 20-residue polypeptide chain whose sequence corresponds to the membrane-bound portion of melittin. The ECEPP/3 (Empirical Conformational Energy Program for Peptides) algorithm was used to describe the conformational energy of the chain. After an exhaustive search involving 14 independent runs, the lowest energy conformation (LEC) (-91.0 kcal/mol) of the entire study was encountered in four of the runs, while conformations higher in energy by no more than 1.8 kcal/mol were found in the remaining runs with the exception of one of them (run 8). The LEC is identical to the conformation found recently by J. Lee, H. A. Scheraga, and S. Rackovsky [(1988) "Conformational Analysis of the 20-Residue Membrane-Bound Portion of Melittin by Conformational Space Annealing," Biopolymers, Vol. 46, pp. 103-115] as the lowest energy conformation obtained in their study using the conformational space annealing method. These results suggest that this conformation corresponds to the global energy minimum of the ECEPP/3 potential function for this specific sequence: it also appears to be the conformation of lowest free energy.

Amino Acid Sequence↗
PubMed1998

Exchange between stacking conformers in a four-Way DNA junction.

Four-way DNA junctions undergo metal ion-induced folding by means of pairwise coaxial stacking of helical arms in one of two possible conformers that depend on the choice of stacking partners. For most such junctions there is a significant bias toward one conformer over the other. In this study we have characterized a four-way DNA junction in which there is rapid exchange between equal populations of the two possible stacking conformers. Analysis of the global conformation using comparative gel electrophoresis gives results consistent with either a tetrahedral disposition of the four arms or an equilibrium between equal populations of the two alternative stacked X-structures. Protection of bases at the center of the junction against attack by osmium tetroxide indicates that base stacking is preserved through the point of strand exchange. Cleavage across the point of strand exchange by the restriction enzyme MboII is consistent with pairwise coaxial stacking of helical arms. Taken together, these indicate that the junction adopts the stacked X-structure, but unusually there appears to be little bias for one stacking conformer over the other. Complete digestion of junctions by MboII demonstrates that all the molecules in solution pass through a given conformer during the time of incubation, demonstrating that exchange between conformers must occur. This is true even for minor stacking conformers in strongly biased junctions. Comparative gel electrophoresis shows that sequence changes at the third position out from the point of strand exchange can have a marked influence on the relative stability of the stacking conformers.

Cations, Divalent↗
PubMed1991

Molecular determinants in the bioactivation of the dopaminergic neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

Nineteen analogs of the dopaminergic neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) have been used as probes to study the structural parameters that influence MAO-catalyzed oxidation. In this study, the efficiency of enzyme-catalyzed substrate oxidation was found to be unrelated to parameters such as the ionization potential, dipole moment, net atomic charge at C5 and the dihedral angle between the phenyl ring and the tetrahydropyridine moiety. Conformational analysis revealed that substitution at the C2' position of MPTP yields atropisomers. It is suggested that one of these atropisomers would be either inactive or substantially less active than the other. Therefore, the relative oxidative efficiency and toxicity of these compounds reported earlier may have been significantly underestimated. Based on the conformational analysis and other data, a rudimentary model of the MAO substrate site has been developed which partially explains the substrate specificities of MAO A and MAO B. Each substrate binding site can be divided into two regions, (a) an amine-binding pocket (for the tetrahydropyridine moiety), and (b) a 'bulky substituent' region (for the phenyl group and its substituents). The length of the substrate binding site (measured along the long axis of MPTP) is approximately 8.5 A, and the width of the 'amine-binding' pocket is approximately 2.5 A (from C3 to C5). The 'bulky substituent' region contains a central area for binding the phenyl group of MPTP. This central area is flanked by two hydrophobic pockets, P2' and P3'. In MAO A, the pocket P2'-A is oriented 45-135 degrees relative to the plane of the tetrahydropyridine moiety, with a radius of 3.1 A from C2' of the phenyl ring. The radius of a similar but smaller pocket, P2'-B, in MAO B, is approximately 2.7 A. In MAO B, the pocket P3'-B (radius 2.36 A from C3') is larger than a similar pocket P3'-A (radius 1.70 A from C3') in MAO A. The foregoing characterization suggests that differences in the size and topography of both of the substituent pockets play an important role in determining the substrate specificities of these two isozymes.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1999

p53 gene mutations in non-small cell lung cancer detected by polymerase chain reaction single-strand conformation polymorphism analysis.

Mutations of the p53 tumor suppressor gene are the most frequent genetic alterations detected in human lung cancer. To assess the pathogenic significance of p53 gene alterations in Chinese non-small cell lung cancer (NSCLC), 74 paired samples of primary lung cancer and normal lung tissue far away from the cancer were analyzed for mutations of the p53 gene (exons 5-8) using exon-specific PCR, single-strand conformation polymorphism (PCR-SSCP). p53 mutations were observed in 55.4% (41/74) of the samples. No linkages were detected between the incidence of p53 mutations and histological type, lymph node metastasis, age or sex. Significant association between p53 mutations and degree of differentiation in adenocarcinomas, not in squamous cell carcinomas, was observed. The frequency of p53 mutations in smokers (65.3%) was higher than in nonsmokers (33.3%) and reached statistical significance. We also found p53 mutations in 6/7 samples which had tissue invasion and distant metastasis. These results suggest that smoking could be an important factor in lung carcinogenesis, p53 mutation is a worse prognosis indicator in adenocarcinomas and related to high aggressive behavior of human lung cancer.

Adenocarcinoma↗
PubMed1994

The pseudo-beta I-turn. A new structural motif with a cis peptide bond in cyclic hexapeptides.

Synthesis and conformational analysis of three cyclic hexapeptides cyclo(-Gly1-Pro2-Phe3-Val4-Xaa5-Phe6), Xaa = Phe (I), D-Phe (II) and D-Pro (III), were carried out to examine the influence of proline on the formation of reverse turns and the dynamics of hydrophobic peptide regions. Assignment of all 1H and 13C resonances was achieved by homo- and heteronuclear 2D-NMR techniques (TOCSY, ROESY, HMQC, HMQC-TOCSY and HMBCS-270). The conformational analysis is based on interproton distances derived from ROESY spectra and homo- and heteronuclear coupling constants (E.COSY, HETLOC and HMBCS-270). For structural refinements restrained molecular dynamics (MD) simulations in vacuo and in DMSO were performed. Each peptide exhibits two conformations in DMSO solution due to cis-trans isomerism about the Gly-Pro peptide bond. Surprisingly the cis-Gly-Pro segment in the minor isomers is not involved in a beta VI-turn, but forms a turn structure with cis-Gly-Pro in the i and i + 1 positions. Although no stabilizing hydrogen bond is found in this turn, the phi- and psi-angles closely correspond to a beta I-turn [Pro2: phi(i + 1) -60 degrees, psi(i + 1) -30 degrees; Phe3: phi(i + 2) -100 degrees, psi(i + 2) -50 degrees]. Hence we call this structural element a pseudo-beta I-turn. As expected, in the dominating all-trans isomers proline occupies the i + 1 position of a standard beta I-turn. Therefore, cis-trans isomerization of the Gly1-Pro2 amide bond only induces a local conformational rearrangement, with minor structural changes in other parts of the molecule. However, the geometry of the other regions is affected by the chirality of the i + 1 amino acid for both isomers (beta I for Phe5, beta II' for D-Phe5 or D-Pro5).

Computer Simulation↗
PubMed1992

[Conformational aspects of the biological effect of functional fragments of the p21ras oncoprotein family. 2. Fragment 1-16, various sequences].

The conformational analysis data on active ([Val12-Gly13], [Asp12-Gly13] and [Gly12-Asp13]) and passive ([Gly12-Gly13] and [Pro12-Gly13]) modifications of the p21ras family oncoproteins are presented. The activating amino acid substitutions are shown to be accompanied by essential changes in the secondary structure, resulted in the 9-16 fragment spiralization. The spatial structure of the 1-9 fragment does not vary for all the predominant forms of the active and passive analogues. The results of the conformational analysis have been used for studying the structural-functional relationships.

Amino Acids↗
PubMed1991

Determination of Duchenne muscular dystrophy carrier status by single strand conformation polymorphism analysis of deleted regions of the dystrophin locus.

The molecular characterisation of the dystrophin gene, mutations in which are responsible for X linked Duchenne and Becker muscular dystrophies, has led to an array of strategies for the diagnosis of affected subjects and carriers. Initially these were based on blotting and hybridisation technologies but have recently been largely superseded by PCR based techniques which afford greater speed and sensitivity. We describe the use of single strand conformation polymorphism to detect heterozygosity in regions of the dystrophin locus which are deleted in affected males, to determine the carrier status of their female relatives.

Dystrophin↗
PubMed1999

Single-strand conformation polymorphism analysis for identification of four members of the Anopheles funestus (Diptera: Culicidae) group.

Members of the Anopheles funestus Giles group are difficult to identify because of the morphological overlap that exists within the group. This inability to distinguish species, as well as the fact that the species vary in their behavior and biting preferences, complicate the successful planning and maintaining of malaria control programs. In this article we discuss the use of a single-strand conformation polymorphism (SSCP) assay to distinguish 4 members of the An. funestus group collected at 10 different localities in Africa. rDNA genes differ at numerous sites among closely related species. Using conserved primers, the D3 domain in the 28S gene was amplified, electrophoresed on SSCP gels, and species-specific patterns were observed. Intraspecific variation was detected in An. funestus specimens from East and West Africa. Analyzing 108 An. funestus, 78 An. vaneedeni Gillies & Coetzee, 21 An. rivulorum Leeson, and 2 An. lessoni Evans, we concluded that SSCPs can be used successfully as a molecular tool for the identification of these species.

Animals↗
PubMed1999

Computer-Aided Design (CAD) of Synzymes: Use of Molecular Mechanics (MM) for the Rational Design of Superoxide Dismutase Mimics.

Mn(II) complexes of C-substituted macrocyclic 1,4,7,10,13-pentaazacyclopentadecane ligands have been shown to be excellent functional mimics (Synzymes) of the native enzyme manganese superoxide dismutase (Mn SOD). To better understand the profound effects that substituents exert on the SOD catalytic activity, we have utilized molecular mechanics (MM) calculations employing the CAChe system. Such a conformational analysis has made it possible to develop a consistent model that correlates catalytic rate with the ability of the ligand to adopt a folded geometry about the high-spin d(5) spherically symmetrical Mn(II) ion, thus affording a six-coordinate pseudo-octahedral geometry (the geometry required by Mn(III)). This conformational analysis is consistent with the model that one of the nitrogen donors of the pentaaza crown ligand folds to occupy a pseudo-axial coordination position of an octahedron. The DeltaE between the lowest energy folded ligand structure about Mn(II) and its corresponding Mn(III) structure correlates with catalytic activity; i.e., for a large series of complexes an excellent correlation is obtained for both the inner-sphere and outer-sphere rate constants for oxidation of Mn(II)-the rate-determining step in the catalytic cycle for these SOD mimics. From single-crystal X-ray structure determinations on several different members of this class of 7-coordinate dichloro(pentaaza crown) Mn(II) complexes, we have observed that the arrangement of NH's of the secondary amine donors is such that they alternate in their relative orientation to the plane generated by the five nitrogens and the Mn; i.e., the NH's are arranged in an up-down-up-down-up stereochemistry. Thus, one side of the plane of the macrocyclic ring possesses two nonadjacent NH's, while the opposite side has three NH's. Two unique folding motifs generated from MM calculations are found to correlate with the two pathways for Mn(II) oxidation: (1) the inner-sphere path correlates with an NH from the side of the two NH's folding into the axial octahedral coordination site, and (2) the outer-sphere path correlates with an NH from the side of the three NH's folded into an axial O(h) site. MM calculations allow one to probe the effect that substituents on the macrocyclic ring carbons have on the relative energies of the Mn(II) and Mn(III) complexes with these ligands in the various potential folded geometries. The details of this modeling paradigm and the results of MM calculations utilizing the folding motif for a large number complexes are described. Of particular significance is the ability of the MM tool to predict correctly that certain substituent patterns and substituents enhance or reduce the contribution of one or the other pathway to the overall catalytic rate. The syntheses of several new complexes are reported and the rate constants for the two pathways of Mn(II) oxidation have been measured and found to correlate with the predictions arising from the energetics of folding as calculated by MM calculations.

Journal Article↗