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At least 595 records · Page 33Linked to original sources
PubMed1996

Conformational analysis of cyclic hexapeptides designed as constrained ligands for the SH2 domain of the p85 subunit of phosphatidylinositol-3-OH kinase.

The structures of the cyclic hexapeptide cyclo(-Gly-Tyr-Val-Pro-Met-Leu-) (1) and its phosphotyrosyl (pTyr) derivative cyclo[-Gly-Tyr(PO3H2)-Val-Pro-Met-Leu-] (2), designed as constrained models of a sequence that interacts with the src homology 2 (SH2) region of the p85 subunit of phosphatidylinositol-3-OH kinase (PI-3 kinase), were studied in methanol/water solutions by 500 MHz nmr spectroscopy. Compound 1 was found to exist as a 2:1 mixture of isomers about the Val-Pro bond (trans and cis prolyl) between 292-330 K in 75% CD3O(D,H)/(D,H)2O solutions. A third species of undetermined structure (ca. 5%) was also observed. Compound 2, a model of phosphorylated peptide ligand that binds to the PI-3 kinase SH2 domain, exhibited similar conformational isomerism. When either compound was dissolved in pure solvent [i.e., 100% CD3O(H,D) or (H,D)2O] the ratio of cis to trans isomers was ca 1:1. A battery of one- and two-dimensional nmr experiments at different temperatures and solvent compositions allowed a complete assignment of both the cis and trans forms of 1 and indicated the trans compound to be the major isomer. The spectral properties of the phophorylated derivative 2 paralleled those of 1, indicating like conformations for the two compounds. Analysis of rotating frame Overhauser spectroscopy data, coupling constants, amide proton temperature dependence, and amide proton exchange rates generated a set of constraints that were employed in energy minimization and molecular dynamics calculations using the CHARMM force field. The trans isomer exists with the tyrosine and C-terminal Tyr(+3) (Met) residues at opposite corners of the 18-membered ring separated by a distance of 16-18 A, in contrast with the cis isomer where the side chains of these residues are much closer in space (7-14 A). It was previously shown that the pTyr and the third amino acid C-terminal to this residue are the critical recognition elements for pTyr-peptide binding to the PI-3 kinase SH2 domain. Such cyclic structures may offer appropriate scaffolding for positioning important amino acid side chains of pTyr-containing peptides as a means of increasing their binding affinities to SH2 domains, and in turn provide a conceptual approach toward the design of SH2 domain directed peptidomimetics.

Amino Acid Sequence↗
PubMed1995

Conformational analysis of helical poly(beta-L-aspartate)s by IR dichroism.

Poly(beta-l-aspartate)s are known to take up helical conformations reminiscent of the alpha-helix of polypeptides. The isobutyl, n-butyl, and 2-methoxyethyl esters have been examined by polarized ir spectroscopy in order to discriminate between the left (1L) and right (2R)-handed conformations, which are known to be compatible with the 13/4-helix adopted by these polyamides when crystallized in the hexagonal form. Dichroic ratios obtained from samples stretched in poly(ethylene oxide) together with orientation measurements made by x-ray diffraction were used to estimate the transition moment directions of amide A, I, and II bands with respect to the fiber axis. These were compared to those calculated by modeling simulations to conclude that the right-handed conformation consisting of 14-membered hydrogen-bonded rings is the correct model for the 13/4-helix. These results give definite support to earlier molecular mechanics calculations, which had shown that the 2R model is energetically favored over the 1L by about 2.5 kcal/(mol residue).

Amino Acid Sequence↗
PubMed1996

Conformational analysis and clustering of short and medium size loops connecting regular secondary structures: a database for modeling and prediction.

Loops are regions of nonrepetitive conformation connecting regular secondary structures. We identified 2,024 loops of one to eight residues in length, with acceptable main-chain bond lengths and peptide bond angles, from a database of 223 protein and protein-domain structures. Each loop is characterized by its sequence, main-chain conformation, and relative disposition of its bounding secondary structures as described by the separation between the tips of their axes and the angle between them. Loops, grouped according to their length and type of their bounding secondary structures, were superposed and clustered into 161 conformational classes, corresponding to 63% of all loops. Of these, 109 (51% of the loops) were populated by at least four nonhomologous loops or four loops sharing a low sequence identity. Another 52 classes, including 12% of the loops, were populated by at least three loops of low sequence similarity from three or fewer nonhomologous groups. Loop class suprafamilies resulting from variations in the termini of secondary structures are discussed in this article. Most previously described loop conformations were found among the classes. New classes included a 2:4 type IV hairpin, a helix-capping loop, and a loop that mediates dinucleotide-binding. The relative disposition of bounding secondary structures varies among loop classes, with some classes such as beta-hairpins being very restrictive. For each class, sequence preferences as key residues were identified; those most frequently at these conserved positions than in proteins were Gly, Asp, Pro, Phe, and Cys. Most of these residues are involved in stabilizing loop conformation, often through a positive phi conformation or secondary structure capping. Identification of helix-capping residues and beta-breakers among the highly conserved positions supported our decision to group loops according to their bounding secondary structures. Several of the identified loop classes were associated with specific functions, and all of the member loops had the same function; key residues were conserved for this purpose, as is the case for the parvalbumin-like calcium-binding loops. A significant number, but not all, of the member loops of other loop classes had the same function, as is the case for the helix-turn-helix DNA-binding loops. This article provides a systematic and coherent conformational classification of loops, covering a broad range of lengths and all four combinations of bounding secondary structure types, and supplies a useful basis for modelling of loop conformations where the bounding secondary structures are known or reliably predicted.

Databases, Factual↗
PubMed1982

Force field conformational analysis of aminofluorene and acetylaminofluorene substituted deoxyguanosine.

The hepatocarcinogen N-hydroxy-2-acetylaminofluorene forms two C8-substituted deoxyguanosine adducts in vivo. The conformation of these adducts, as well as 2'-deoxyguanosine and 8-amino-2'-deoxyguanosine has been studied with Allinger's force field. Using the glycoside rotation as a reaction coordinate, multidimensional potential energy surface were determined by relaxing all internal degrees of freedom. The calculations indicate the 2'-deoxyguanosine should exist as a mixture of syn and anti forms, that the syn form is slightly favored for 8-amino-2'-deoxyguanosine, that N-(deoxyguanosin-8-yl)-2-acetylaminofluorene (dG-C8-AAF) will only be found in the syn conformation and that, although the syn form is also more stable for N-(deoxyguanosin-8-yl)-2-aminofluorene (dG-C8-AF), it will have a substantially greater proportion of the anti-conformer than is found with dG-C8-AAF. The results of the force field calculations are discussed in relation to the effects these adducts may have on DNA structure.

2-Acetylaminofluorene↗
PubMed1991

Mass-weighted molecular dynamics simulation and conformational analysis of polypeptide.

Atomic motions in protein molecules have been studied by molecular dynamics (MD) simulations; dynamics simulation methods have also been employed in conformational studies of polypeptide molecules. It was found that when atomic masses are weighted, the molecular dynamics method can significantly increase the sampling of dihedral conformation space in such studies, compared to a conventional MD simulation of the same total simulation time length. Herein the theoretical study of molecular conformation sampling by the molecular dynamics-based simulation method in which atomic masses are weighted is reported in detail; moreover, a numerical scheme for analyzing the extensive conformational sampling in the simulation of a tetrapeptide amide molecule is presented. From numerical analyses of the mass-weighted molecular dynamics trajectories of backbone dihedral angles, low-resolution structures covering the entire backbone dihedral conformation space of the molecule were determined, and the distribution of rotationally stable conformations in this space were analyzed quantitatively. The theoretical analyses based on the computer simulation and numerical analytical methods suggest that distinctive regimes in the conformational space of the peptide molecule can be identified.

Amino Acid Sequence↗
PubMed1993

Conformational analysis of [D-Ala9]alpha-factor and [L-Ala9]alpha-factor in solution and in the presence of lipid.

The conformations in solution and in the presence of lipid vesicles of [D-Ala9] and [L-Ala9] analogues of the alpha-factor (WHWLQLKPGQPMY) from the yeast Saccharomyces cerevisiae were examined by NMR spectroscopy. Although both peptides are flexible molecules, NOE and NH d delta/dT data indicate that the [D-Ala9]alpha-factor analogue in DMSO and aqueous solution adopts a type II beta-turn about residues 8 and 9. In contrast, various NMR parameters for the less active [L-Ala9] analogue do not provide evidence for a regular secondary structure in solution. Transfer NOE data indicate that for both peptides binding to the lipid is strongest for the N-terminal residues. The C-terminus of the [D-Ala9] analogue appears to be more constrained in the bound state than the C-terminus of the [L-Ala9] analogue. This result is consistent with transfer NOE evidence that the type II beta-turn conformation of the [D-Ala9]alpha-factor is maintained in the lipid bound state.

Amino Acid Sequence↗
PubMed1994

Conformational analysis of the Saccharomyces cerevisiae tridecapeptide mating pheromone by 13C,15N rotational-echo double resonance nuclear magnetic resonance spectroscopy.

The solid-state conformation of [Nle12]alpha-factor, the Saccharomyces cerevisiae tridecapeptide mating pheromone (WHWLQLKPGQPNleY), was investigated by 13C,15N rotational-echo double resonance (REDOR) nuclear magnetic resonance spectroscopy (NMR). Previous high-resolution NMR studies of [Nle12]alpha-factor in solution revealed a transient Type II beta-turn spanning residues 7-10 of the peptide. To investigate this region of [Nle12]alpha-factor in the solid state, a series of four selectively 13C,15N-enriched tridecapeptides were synthesized by solid-phase methods. Carbon-nitrogen distances between the labeled sites in lyophilized samples of [Nle12]alpha-factor were accurately measured by REDOR NMR. Experimentally determined distances were compared with those from calculated models for Type I and Type II beta-turns and for an extended chain. The measured distances indicate that, in a lyophilized powder, the central region of the [Nle12]alpha-factor is not in an extended conformation. The experimental data was most consistent with distances obtained from a distorted Type I beta-turn model.

Amino Acid Sequence↗
PubMed2003

Modeling NMR parameters by DFT methods as an aid to the conformational analysis of cis-fused 7a(8a)-methyl octa(hexa)hydrocyclopenta[d][1,3]oxazines and [3,1]benzoxazines.

The energies of the preferred conformations of four 7a-methyl octa(or hexa)hydrocyclopenta[d][1,3]oxazines, five 8a-methyl octa(or hexa)hydro[3,1]benzoxazines, and 8a-methyl hexahydro[1,3]benzoxazinone, all cis-fused, were investigated by DFT methods. Following geometry optimization at the B3LYP/6-31G(d,p) level, both the proton chemical shifts and the vicinal coupling constants between H-4a and the H-4 and H-5 protons were calculated at the B3LYP/cc-pVTZ level and compared to the previously experimentally measured values. The agreement between the calculated and the experimental chemical shifts was found to be good. Similarly, the agreement between the calculated and the experimental vicinal coupling constants was also found to be good, thus providing a methodology for determining the conformational equilibria of such systems that is comparable in many respects to experimental approaches such as variable-temperature NMR or to the use of model coupling constant values, when available, from analogous compounds.

Journal Article↗
PubMed2006

Synthesis and conformational analysis of new cyclobutane-fused nucleosides.

[structure: see text]. A stereselective synthesis of 3-oxabicyclo[3.2.0]heptane nucleoside analogues, which were designed as conformational mimics of the anti-HIV agents 2',3'-didehydro-2',3'-dideoxythimidine (stavudine, d4T) and 2',3'-didehydro-2',3'-dideoxyadenosine (d4A), is described. The target compounds were prepared by condensation of a common intermediate bicyclic acetate, derived from a homochiral 2(5H)-furanone, with pyrimidine and purine bases under modified Vorbrüggen conditions. The conformational behavior of the synthesized nucleoside analogues was studied by NMR spectroscopy and X-ray crystallography.

Anti-HIV Agents↗
PubMed1993

Conformational analysis of the opioid phenylmorphan and its 9 alpha-methyl analogue in solution using high-resolution nuclear magnetic resonance spectroscopy.

The solution conformations of the opioid phenylmorphan (5-m-hydroxyphenyl-2-methylmorphan) and its 9 alpha-methyl analogue were studied using one- and two-dimensional high resolution NMR techniques. The NMR spectra were analyzed by interpreting the phase-sensitive 2-D COSY and double quantum filtered COSY spectra, 1H-1H vicinal coupling constants, and nuclear Overhauser effects in the phase-sensitive 2-D NOESY spectra. The results show that, for both compounds, a chair-chair conformation of the cyclohexane and piperidine rings is exclusively preferred with some distortion of the rings from perfectly staggered chairs. For phenylmorphans, the phenyl ring is oriented to fit into the cleft formed by the cyclohexane and piperidine rings. Thus, for the (+)-enantiomer, the phenyl group assumes the same orientation with regard to the piperidine ring as morphine consistent with the morphine-like properties of the compound. For the 9 alpha-methyl analogue, the plane of the phenyl ring essentially bisects the piperidine ring to which it is attached and is outside of the required range of opioid agonists. This is consistent with the atypical properties of the two enantiomers. The NMR results are compared to the conformations of (-)-phenylmorphan and the (+)-9 alpha-methyl analogue in the crystal state and to the results of molecular mechanics (MM2) studies.

Ligands↗