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PubMed2003

Simultaneous determination of bioactive conformations and alignment rules by multi-way PLS modeling.

In this study, we propose a new three-dimensional quantitative structure-activity relationship (3D-QSAR) method for selecting bioactive conformations and alignment rule simultaneously. The possible conformations of all molecules are generated by conformational analysis and they are superimposed on template conformer with possible alignment rules. The field variables are calculated as 3D descriptor of structures. Four-way partial least-squares (PLS) analysis is applied, and the conformations and alignment rule largely contributing to biological activity are selected. In order to demonstrate this method, the data set of benzodiazepine derivatives, antagonists of (CCK-B), was used as a test sample. As a result, appropriate conformers and alignment rule were selected and significant PLS model was obtained. The resulting final model could give the reasonable 3D coefficient contour maps. Moreover, external prediction was carried out by use of external data sample and its prediction was proved to be high enough.

Algorithms↗
PubMed1998

Mutation analysis of the human homologue of Drosophila patched and the xeroderma pigmentosum complementation group A genes in squamous cell carcinomas of the skin.

The human homologue of Drosophila patched (PTCH), located at chromosome 9q22.3, was recently identified as a candidate tumor suppressor gene for familial and sporadic basal cell carcinomas. Squamous cell carcinomas (SCCs) of the skin display allelic loss in this chromosomal region, which, in addition to the PTCH gene, contains the DNA repair gene xeroderma pigmentosum complementation group A (XPA). Patients with xeroderma pigmentosum are predisposed to non-melanoma skin tumors because of deficient excision repair of ultraviolet-induced DNA damage. Mutation analysis by single-strand conformation analysis and direct DNA sequencing of all 23 exons of the PTCH gene and all six exons of the XPA gene in 14 SCCs did not reveal structural alterations in any of these genes. Additionally, analysis of PTCH expression by in situ hybridization in SCCs revealed no evidence of upregulation of PTCH mRNA, confirming the lack of mutations in this gene. These findings suggest that another, yet to be identified gene or genes on chromosome 9q are involved in SCC tumorigenesis.

Carcinoma, Squamous Cell↗
PubMed1990

[Three-dimensional structure of the lipotropic active fragment of sea whale somatotropin].

Using semiempirical conformational analysis method, the spatial structure and conformational properties of the sea-whale somatotropin lipotropic action were investigated. The calculations were based on the fragmental analysis using non-valent, electrostatic interactions, torsional barriers and hydrogen bonds. The computer data suggest that this molecule can exist only in several low energy conformational states. The experimental results can be used for the analysis of structural-and-functional relationships.

Amino Acid Sequence↗
PubMed2000

Molecular recognition templates of peptides: driving force for molecular evolution of peptide transporters.

Small peptides derived from protein hydrolysis occur ubiquitously. To utilize these structurally diverse compounds, organisms possess generic peptide transporters for di- (Dpp), tri- (Tpp), and oligopeptides (Opp). Using conformational analysis, we describe the predominant conformers of di-, tri-, and oligopeptides in water; dipeptides occur as nine main groups, defined by specific combinations of torsional angles. The molecular recognition templates (MRTs) of substrates for Dpp and Tpp comprise distinct groups of dipeptide conformers plus folded tripeptide conformers with matching spatial distribution of recognition features; for Opp, the MRT involves specific oligopeptide conformers with extended backbones. For any peptide, the proportion of its conformers in a particular MRT correlates with its relative binding and transport by each transporter. Thus, peptide transporters have evolved complementary specificities to optimize utilization of the universal peptide pool. The general applicability of MRTs should facilitate rational design and targeting of peptide-based prodrugs.

Carrier Proteins↗
PubMed2000

D-LysAsnProTyr tetrapeptide: a novel B-cell stimulant and stabilized bursin mimetic.

The tetrapeptide I (D-lysine-L-asparaginyl-L-prolyl-L-tyrosine or D-LysAsnProTyr), and analogue sequences, were synthesized and evaluated for the ability to stimulate immune cell subsets. These sequences were selected based on their perceived ability to readily adopt a beta-turn structure. In vitro immunological assays revealed a robust stimulation of mitogen activated B-cell proliferation and a modest to significant stimulation of cytotoxic T lymphocytes (CTLs). Further, this in vitro stimulation of B-cells was accompanied by an in vivo expansion of B-cells in C57BL/6 mice, as demonstrated by immunophenotyping experiments. Interestingly, a conformational analysis of the low energy conformers of I and the endogenous B-cell stimulant bursin (LysHisGlyNH2) shows that these molecules can be superimposed. However, I displayed significantly enhanced physiological stability. For a number of reasons, I may be a particularly useful vaccine adjuvant.

Animals↗
PubMedDate not supplied

Conformational study in water by NMR and molecular modeling of cyclic glutamic acid analogues as probes of vitamin K dependent carboxylase.

The conformational analysis of four glutamic acid analogues containing a cyclopentyl or cyclohexyl ring, substituted in position 1 by a BOC protected amino group and a methyl ester group and in position 3 by a free carboxylate group, has been carried out in an aqueous environment, by 1H and 13C NMR spectroscopy, and molecular dynamics (MD). Their structural properties were under investigation for a structure-activity relationship analysis to determine the preferred conformation in the carboxylase active site. For each compounds, resulting conformations from NMR and MD data were analyzed and classified according to the dihedral angles chi 1 and chi 2, the distances and the spatial distribution involving charged or substituted C- and N-terminal groups. A reduced number of conformational families were found to be in qualitative agreement with NMR and MD data. A comparison between these different classes of the active and nonactive derivatives was achieved.

Animals↗
PubMed1994

Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man.

BACKGROUND AND METHODS: Mutations in the estrogen-receptor gene have been thought to be lethal. A 28-year-old man whose estrogen resistance was caused by a disruptive mutation in the estrogen-receptor gene underwent studies of pituitary-gonadal function and bone density and received transdermal estrogen for six months. Estrogen-receptor DNA, extracted from lymphocytes, was evaluated by analysis of single-strand-conformation polymorphisms and by direct sequencing. RESULTS: The patient was tall (204 cm [80.3 in.]) and had incomplete epiphyseal closure, with a history of continued linear growth into adulthood despite otherwise normal pubertal development. He was normally masculinized and had bilateral axillary acanthosis nigricans. Serum estradiol and estrone concentrations were elevated, and serum testosterone concentrations were normal. Serum follicle-stimulating hormone and luteinizing hormone concentrations were increased. Glucose tolerance was impaired, and hyperinsulinemia was present. The bone mineral density of the lumbar spine was 0.745 g per square centimeter, 3.1 SD below the mean for age-matched normal women; there was biochemical evidence of increased bone turnover. The patient had no detectable response to estrogen administration, despite a 10-fold increase in the serum free estradiol concentration. Conformation analysis of his estrogen-receptor gene revealed a variant banding pattern in exon 2. Direct sequencing of exon 2 revealed a cytosine-to-thymine transition at codon 157 of both alleles, resulting in a premature stop codon. The patient's parents were heterozygous carriers of this mutation, and pedigree analysis revealed consanguinity. CONCLUSIONS: Disruption of the estrogen receptor in humans need not be lethal. Estrogen is important for bone maturation and mineralization in men as well as women.

Adult↗
PubMed1989

Correlation of beta-bend conformations of tetrapeptides with their activities in CD4-receptor binding assays.

Conformational analysis, based on ECEPP (Empirical Conformational Energy Program for Peptides) using the chain build-up procedure, was applied to determine the low-energy conformations for a series of tetrapeptides. The tetrapeptides are components of larger peptides which have been found to bind to the CD4 receptor of monocytes. Several previous studies have implicated the tetrapeptide units investigated here as being critical to the biological activities of the full peptides. Five such tetrapeptides were studied: Ser-Ser-Asn-Tyr (from ribonuclease A), Thr-Thr-Asn-Tyr (from peptide T, known to block human immunodeficiency virus from attaching to CD4+ T cells), Thr-Ile-Asn-Tyr (from polio virus coat protein, which is less active than the other peptides in binding to CD4 receptors), Ser-Ser-Ala-Tyr (from the gp 120 coat protein of human immunodeficiency virus, a variant of the peptide T sequence, active in blocking viral attachment to CD4+ cells), and the tetrapeptide from an active synthetic pentapeptide, Asn-Thr-Lys-Tyr (from Asn-Thr-Lys-Tyr-Thr). Using a 7 kcal/mol cutoff, the low-energy conformations for each peptide were computed. Approximately 20,000 conformations were computed for each tetrapeptide. Residue probability profiles were determined for each tetrapeptide. All tetrapeptides except for the polio sequence showed flexibility in the sense that many low-energy conformations were possible. In previous studies, it was postulated that the critical tetrapeptide units would adopt conformations similar to the one observed in a segment of ribonuclease A, residues 22-25, a beta-bend, which is part of an octapeptide segment (residues 19-26) that is homologous to the sequence of peptide T.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1978

Nuclear-magnetic-resonance studies of 5'-ribonucleotide and 5'-deoxyribonucleotide conformations in solution using the lanthanide probe method.

The conformations of the metal-bound 5'-ribonucleotides and 5'-deoxyribonucleotides in aqueous solution at different pH values have been studied using the lanthanide probe method. The conformational analysis, based on mixing different conformations in fast exchange within the nuclear magnetic resonance time scale, agrees well with the results from coupling constants, nuclear Over-hauser effects and spin-lattice relaxation times, obtained for the metal-fixed systems. The equilibrium between the two basic conformational combinations for the 5'-nucleotides, anti-(N in equalibrium S)-gg-g'g' and syn-(N in equalibrium S)-gt-g'g' depends on the nature of the furanose ring, the base and also on the state of base protonation and phosphate ionization. The effect of base protonation is particularly strong for the guanine nucleotides.

Adenosine Monophosphate↗
PubMed1979

Nuclear-magnetic-resonance study of the conformation of a dinucleotide in solution using the lanthanide probe method.

The conformation of the dinucleotide adenylyl(3'-5')adenosine 2'-phosphate (ApA2'p) in aqueous solution at different pH values and temperatures has been studied using the lanthanide(III) ethylenodiaminetetraacetate(EDTA) 1:1 complexes as shift and relaxation probes. The conformational analysis, based on mixing different conformations in fast exchange within the nuclear magnetic resonance time scale, agrees well with the results from vicinal coupling constants and dimerization shifts obtained for the metal-free system. The dinucleotide exists in a temperature-dependent and pH-dependent conformational equilibrium between unstacked and base-stacked forms. At neutral pH and low temperature, the stacked form predominates, and it is a predominantly right helical structure, characterized as an anti, 3E, g-, g- g-, g'g', gg, 3E, anti conformation. This situation contrasts with adenylyl(3'-5')adenosine (ApA), where both right and left helices contribute to the stacked form. The nucleotidyl units of the unstacked form of ApA2'p have average conformations which are very similar to those of the corresponding mononucleotides in similar conditions.

Adenosine↗
PubMed2005

Rapid self-assembly of DNA on a microfluidic chip.

BACKGROUND: DNA self-assembly methods have played a major role in enabling methods for acquiring genetic information without having to resort to sequencing, a relatively slow and costly procedure. However, even self-assembly processes tend to be very slow when they rely upon diffusion on a large scale. Miniaturisation and integration therefore hold the promise of greatly increasing this speed of operation. RESULTS: We have developed a rapid method for implementing the self-assembly of DNA within a microfluidic system by electrically extracting the DNA from an environment containing an uncharged denaturant. By controlling the parameters of the electrophoretic extraction and subsequent analysis of the DNA we are able to control when the hybridisation occurs as well as the degree of hybridisation. By avoiding off-chip processing or long thermal treatments we are able to perform this hybridisation rapidly and can perform hybridisation, sizing, heteroduplex analysis and single-stranded conformation analysis within a matter of minutes. The rapidity of this analysis allows the sampling of transient effects that may improve the sensitivity of mutation detection. CONCLUSIONS: We believe that this method will aid the integration of self-assembly methods upon microfluidic chips. The speed of this analysis also appears to provide information upon the dynamics of the self-assembly process.

Journal Article↗
PubMed1991

[Conformational-functional relationships of tetragastrin analogs].

Sets of low-energy backbone conformations of the active tetragastrin analogue Boc-Trp-Leu-Asp-Phe-NH2 and two competitive antagonists Boc-Trp-Leu psi (CH2NH)-Asp-Phe-NH2 and Boc-Trp-Leu-Asp-O-CH2-CH2-C6H5 were obtained using theoretical conformational analysis methods. Groups of the conformations were selected for the three analogues, allowing a spatial matching of Trp, Asp and Phe residues responsible for the gastrin receptor binding. Three conformations possessing the lowest energies among the geometrically similar structures of these three peptides are suggested as a model for the "receptor-bound" conformations of these analogues. Backbone spatial folding resembling an alpha-helix turn is characteristic of these conformations. The correspondence of the proposed model to the available data on structure--activity relationships for tetragastrin analogues is discussed. Orientations of the putative receptor-bound conformations in a "water--lypophylic medium" two-phase system were investigated.

Amino Acid Sequence↗
PubMed1998

[Structural organization of 2C-terminal region and its analogs in a subunit of ribonucleotide reductase from herpes virus].

By means of conformational analysis, the spatial structure and conformational potential of the H-Tyr-Ala-Gly-Ala-Val-Val-Asn-Asp-Leu-OH molecule, which corresponds to sequence 329-337 of the subunit 2 C-terminal region of the herpes virus ribonucleotide reductase, were studied. It was shown that its spatial organization can be described by a set of 17 low-energy conformations of the backbone. The "reverse conformational problem" for this molecule was solved to enable the prediction of a series of synthetic analogues matching the set of low-energy, potentially physiologically active conformations.

Amino Acids↗
PubMed1998

Pharmacophoric search and 3D-QSAR comparative molecular field analysis studies on agonists of melatonin sheep receptors.

Conformational analysis was used to characterize the agonist pharmacophore for melatonin sheep brain receptor recognition and activation. The molecular geometry shared by all conformations of the selected active ligands was determined. Assuming that all the compounds interact at the same binding site at the receptor level, 2-iodomelatonin pharmacophoric conformation served as a template for the superimposition of 64 structurally heterogeneous agonists constituting the training set used to perform a three-dimensional quantitative structure-activity relationship study via the comparative molecular field analysis method. A statistically significant model was obtained for the totality of the compounds (n = 64, q2 = 0.62, N = 6, r2 = 0.96, s = 0.28, F = 249) with steric, electrostatic, and lipophilic relative contributions of 28%, 35%, and 37%, respectively. The predictive power of the proposed model was discerned by successfully testing the 78 agonist ligands constituting the test set. The model so obtained and validated brings important structural insights to aid the design of novel melatoninergic agonist ligands prior to their synthesis.

Animals↗
PubMed2005

Analysis of the contribution of reverse transcriptase and integrase proteins to retroviral RNA dimer conformation.

All retroviruses contain two copies of genomic RNA that are linked noncovalently. The dimeric RNA of human immunodeficiency virus type 1 (HIV-1) undergoes rearrangement during virion maturation, whereby the dimeric RNA genome assumes a more stable conformation. Previously, we have shown that the packaging of the HIV-1 polymerase (Pol) proteins reverse transcriptase (RT) and integrase (IN) is essential for the generation of the mature RNA dimer conformation. Analysis of HIV-1 mutants that are defective in processing of Pol showed that these mutant virions contained altered dimeric RNA conformation, indicating that the mature RNA dimer conformation in HIV-1 requires the correct proteolytic processing of Pol. The HIV-1 Pol proteins are multimeric in their mature enzymatically active forms; RT forms a heterodimer, and IN appears to form a homotetramer. Using RT and IN multimerization defective mutants, we have found that dimeric RNA from these mutant virions has the same stability and conformation as wild-type RNA dimers, showing that the mature enzymatically active RT and IN proteins are dispensable for the generation of mature RNA dimer conformation. This also indicated that formation of the mature RNA dimer structure occurs prior to RT or IN maturation. We have also investigated the requirement of Pol for RNA dimerization in both Mason-Pfizer monkey virus (M-PMV) and Moloney murine leukemia virus (MoMuLV) and found that in contrast to HIV-1, Pol is dispensable for RNA dimer maturation in M-PMV and MoMuLV, demonstrating that the requirement of Pol in retroviral RNA dimer maturation is not conserved among all retroviruses.

Dimerization↗
PubMed1998

Travelling through conformational space: an approach for analyzing the conformational behaviour of flexible molecules.

The applications of the single-co-ordinate-driving (SCD) method in conformational analysis of flexible molecules have been discussed. SCD can best be characterised as travelling through low energy areas of the conformational space. It has been shown that SCD provides detailed information about the conformational behaviour of small and middle sized flexible molecules. It has been demonstrated that SCD may fail for molecules which are more rigid but still conformationally interesting, for example, AUG trimer of RNA. It has been found out that the search problems are eliminated when SCD is coupled with simulated annealing (SCD-SA). Both SCD and SCD-SA methods may be recognised as successful tools for analysis of conformational space. It has been demonstrated, how SCD and SCD-SA results can be used as a background to discover and analyse correlated conformational processes, to quantify molecular conformational flexibility, and to provide an appropriate background for an efficient free energy simulation.

Computer Simulation↗
PubMed1999

[Mechanism of action of aspartic proteinases. V. Conformational characteristics of fragments of substrate-binding sites in rhizopuspepsin and HIV-1 proteinase].

The conformational states of side chains of catalytic Asp residues in active sites of HIV-1 protease and rhizopuspepsin in the potential field of free enzymes were studied by using theoretical conformational analysis. Structural factors that stabilize the conformation of these residues in free enzymes were revealed. Methods of molecular mechanics were used to estimate the stabilization energy of the Met46-Phe53 labile fragments of HIV-1 protease in the potential field of their nearest surrounding amino acid residues for the conformations characteristic of the free protein and similar to that of the protein in enzyme-inhibitor complexes. In solution, the conformational state of the fragments of the free enzyme was concluded to be similar to that observed in the enzyme complex with the ligand and different from that determined by X-ray diffraction analysis. This difference was ascribed to the effect of crystal packing.

Aspartic Acid Endopeptidases↗
PubMed2001

Flexibility and extensibility in the titin molecule: analysis of electron microscope data.

Muscle elasticity derives directly from titin extensibility, which stems from three distinct types of spring-like behaviour of the I-band portion of the molecule. With progressively greater forces and sarcomere lengths, the molecule straightens and then unfolds, first in the PEVK-region and then in individual immunoglobulin domains. Here, we report quantitative analysis of flexibility and extensibility in isolated titin molecules visualized by electron microscopy. Conformations displayed by molecules dried on a substrate vary from a random coil to rod-like, demonstrating highly flexible and easily deformable tertiary structure. The particular conformation observed depends on the "wettability" of the substrate during specimen preparation: higher wettability favours coiled conformations, whereas lower wettability results in more extended molecules. Extension is shown to occur during liquid dewetting. Statistical methods of conformational analysis applied to a population of coiled molecules gave an average persistence length 13.5(+/-4.5) nm. The close correspondence of this value to an earlier one from light-scattering studies confirms that conformations observed by microscopy closely reflected the equilibrium conformation in solution. Analysis of hydrodynamic forces exerted during dewetting also indicates that the force causing straightening of the molecules and extension of the PEVK-region is in the picoNewton range, whereas unfolding of the immunoglobulin and fibronectin domains may require forces about tenfold higher. The microscope data directly illustrate the relationship between titin conformation and the magnitude of applied force. They also suggest the presence of torsional stiffness in the molecule, which may affect considerations of elasticity.

Animals↗