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At least 217 records · Page 12Linked to original sources
PubMed1994

Nucleic acid modeling tool (NAMOT): an interactive graphic tool for modeling nucleic acid structures.

The helical nature of the molecule (almost all of the DNA and a significant portion of the RNA) makes the modeling of nucleic acids a unique task. Unlike other biopolymers (proteins, lipids, etc.), the integrity the structure of a nucleic acid molecule depends strongly on the maintenance of the base pairing within the molecule. Structural alterations (bending, stretching, compressing, etc.), in general, should not disturb the base pairings. A custom-made molecular modeling tool is developed taking into consideration this specific property of the molecule. Instead of Cartesian coordinates, the modeling is carried out on a set of reduced coordinates developed here in our laboratory. One of the advantages using this set of reduced coordinates is the readiness of maintaining the base pairings while altering the structure. A graphic routine is incorporated into the package to display the image of the molecule while the modeling work is being executed. The program is written in C using XView tool kit with Xlib routines to ensure portability to different workstations.

Algorithms↗
PubMed2000

An experimental and theoretical study of the gas-phase decomposition of monoprotonated peptide nucleic acids.

Peptide nucleic acids (PNAs) are DNA/RNA mimics which have recently generated considerable interest due to their potential use as antisense and antigene therapeutics and as diagnostic and molecular biology tools. These synthetic biomolecules were designed with improved properties over corresponding oligonucleotides such as greater binding affinity to complementary nucleic acids, enhanced cellular uptake, and greater stability in biological systems. Because of the stability and unique structure of PNAs, traditional sequence confirmation methods are not effective. Alternatively, electrospray ionization coupled with Fourier transform ion cyclotron resonance mass spectrometry shows great potential as a tool for the characterization and structural elucidation of these oligonucleotide analogs. Extensive gas-phase fragmentation studies of a mixed nucleobase 4-mer (AACT) and a mixed nucleobase 4-mer with an acetylated N-terminus (N-acetylated AACT) have been performed. Gas-phase collision-induced dissociation of PNAs resulted in water loss, cleavage of the methylene carbonyl linker containing a nucleobase, cleavage of the peptide bond, and the loss of nucleobases. These studies show that the fragmentation behavior of PNAs resembles that of both peptides and oligonucleotides. Molecular mechanics (MM+), semiempirical (AM1), and ab initio (STO-3G) calculations were used to investigate the site of protonation and determine potential low energy conformations. Computational methods were also employed to study prospective intramolecular interactions and provide insight into potential fragmentation mechanisms.

Acetylation↗
PubMed1994

Protection against malaria by immunization with a Plasmodium yoelii circumsporozoite protein nucleic acid vaccine.

Nucleic acid vaccines provide an exciting new alternative approach to developing the multiantigen vaccines designed to induce protective antibody and T-cell responses against Plasmodium proteins that many experts believe will be required for effective protection against malaria. As a first step in this process, we produced a plasmid DNA vaccine that includes the gene encoding the P. yoelii circumsporozoite protein (PyCSP). This vaccine induced higher levels of antibodies and cytotoxic T lymphocytes against PyCSP than immunization with irradiated sporozoites, and protected 9 of the first 16 mice immunized. Work is now in progress to optimize immunization regimens, establish the mechanisms of protective immunity induced by the vaccine, and to determine whether protective immunity can be increased by vaccinating with multiple nucleic acid vaccines designed to produce immune responses against multiple targets.

Amino Acid Sequence↗
PubMed2002

Targeted nucleotide exchange in Saccharomyces cerevisiae directed by short oligonucleotides containing locked nucleic acids.

Locked nucleic acids (LNAs) are novel base modifications containing a methylene bridge uniting the 2'-oxygen and the 4'-carbon. In this study, LNA-modified single-stranded molecules directed the repair of single base mutations in a yeast chromosomal gene. Using a genetic assay involving a mutant hygromycin-resistance gene, correction of point and frameshift mutations was facilitated by vectors containing an LNA residue on each terminus. Increasing the number of LNA bases on each terminus reduced the correction frequency progressively. When the LNA vector is used in combination with a phosphorothioate-modified vector (74-mer), however, a high level of gene-repair activity occurs; hence, short LNA-based vectors can augment the activity of other types of targeting vectors. These data suggest that oligonucleotides containing locked nucleic acid residues can be used to direct single nucleotide exchange reactions in vivo.

Amino Acid Sequence↗
PubMed1986

Algorithms for the search of amino acid patterns in nucleic acid sequences.

Some algorithms are described for the search of regions in a nucleic acid sequence that, when translated into amino acids, are homologous to a given amino acid pattern. All algorithms are modifications of the dynamic programming method for sequence comparison such that the translation of codons is taken into account. One of the algorithms has been implemented as a FORTRAN 77 program. The program operates on files that follow the format of the EMBL Nucleotide Sequence Data Library.

Amino Acid Sequence↗
PubMed1983

Design of immobile nucleic acid junctions.

Nucleic acids that interact to generate structures in which three or more double helices emanate from a single point are said to form a junction. Such structures arise naturally as intermediates in DNA replication and recombination. It has been proposed that stable junctions can be created by synthesizing sets of oligonucleotides of defined sequence that can associate by maximizing Watson-Crick complementarity (Seeman N. C., 1981, Biomolecular Stereodynamics. Adenine Press, New York. 1: 269-278; Seeman, N. C., 1982, J. Theor. Biol. 99:237-247.) To make it possible to design molecules that will form junctions of specific architecture, we present here an efficient algorithm for generating nucleic acid sequences that optimize two fundamental properties: fidelity and stability. Fidelity refers to the relative probability of forming the junction complex relative to all alternative paired structures. Calculations are described that permit approximate prediction of the melting curves for junction complexes.

DNA↗
PubMed2004

Effect of LNA modifications on small molecule binding to nucleic acids.

Locked nucleic acid (LNA) is a conformationally constrained DNA analogue that exhibits exceptionally high affinity for complementary DNA and RNA strands. The deoxyribose sugar is modified by a 2'-O, 4'-C oxymethylene bridge, which projects into the minor groove. In addition to changing the distribution of functional groups in the groove and the overall helical geometry relative to unmodified DNA, the bridge likely alters the hydration of the groove. Each of these factors will impact the ability of small molecules, proteins and other nucleic acids to recognize LNA-containing hybrids. This report describes the ability of several DNA-intercalating ligands and one minor groove binder to recognize LNA-DNA and LNA-RNA hybrid duplexes. Using UV-vis, fluorescence and circular dichroism spectroscopies, we find that the minor groove binder as well as the intercalators exhibit significantly lower affinity for LNA-containing duplexes. The lone exception is the alkaloid ellipticine, which intercalates into LNA-DNA and LNA-RNA duplexes with affinities comparable to unmodified DNA-DNA and RNA-DNA duplexes.

Bisbenzimidazole↗
PubMed2002

Histidine containing peptides and polypeptides as nucleic acid vectors.

Nucleic acid transfer in mammalian cels is drastically improved with devices which increase their delivery in the cytosol upon endocytosis. In this chapter, we describe the effect on plasmid DNA (pDNA) and oligonucleotide (ODN) transfer, of an histidine-rich peptide (H5WYG), histidylated oligolysine (HoK), and histidylated polylysine (HpK) designed on the basis of the membrane destabilization capacity of poly-L-histidine at a pH dose to that of the endosomes. We report that H5WYG, which permeabilizes the cell membrane at pH 6.4, favors the transfection mediated by lactosylated polylysine/pDNA complexes and, by lowering the pH of extracellular medium, allows the loading of the cytosol and the cell nucleus with ODN. We show that HoK forms small cationic spherical particles of 35 nm with ODN and HpK rod or toroid cationic particles of 100 nm with pDNA. PEGylation stabilizes these particles at physiological salt concentration. We also show that (i) HoK/ODN complexes yield a more than 20-fold increase of the biological activity of antisense ODN towards the inhibition of transient as well as constitutive gene expression and (ii) HpK/pDNA complexes yield a transfection efficiency of 3-4.5 order of magnitude higher than do polylysine/pDNA complexes. We also provide evidence that the effect of these polyhistidylated molecules is mediated by imidazole protonation in endosomes. Overall our data show that polyhistidylated molecules constitute interesting devices for an efficient cytosolic delivery of nucleic acids, and that ionic complexes between histidylated polylysine and a pDNA are attractive for developing a nonviral gene delivery system.

Amino Acid Sequence↗
PubMed2000

Antisense inhibition of delta-opioid receptor gene function in vivo by peptide nucleic acids.

Peptide nucleic acids (PNA) are synthetic analogs of DNA that hybridize to complementary oligonucleotide sequences with exceptional affinity and target specificity. The stability of PNA in biological fluids together with the unique hybridization characteristics of these structures suggests that PNA may have considerable potential as antisense agents for experimental use in vivo. To test this hypothesis, we attempted to modulate supraspinal delta-opioid receptor function in rats using PNA sequences designed to be complementary to a region of the rat delta-opioid receptor. Repeated i.c.v. administration of PNA over a period of 5 days significantly inhibited the antinociceptive response and locomotor response to selective delta-opioid receptor agonists. PNA attenuated delta-opioid receptor function in a sequence-specific, target-specific, and reversible manner characteristic of the functional inhibition caused by an antisense mechanism. There were no apparent toxicities arising from the PNA treatment based on the behavior of the animals and inspection of the treated tissues. Saturation binding studies on brain homogenates did not reveal any significant difference in receptor B(max) between treatment groups. However, [(35)S]guanosine-5'-O-(3-thio)triphosphate binding assays demonstrated a significant decrease in agonist efficacy in homogenates prepared from antisense-treated rats. Taken together, these results demonstrate that peptide nucleic acids are effective antisense agents in vivo and suggest that PNA may be a useful alternative to phosphodiester or phosphorothioate oligonucleotides, or variants thereof, for determination of gene function in vivo.

Analgesics↗
PubMed1978

Chromic-acid formaldehyde fixation of nucleic acids of bacteriophage phi6 and infectious bovine rhinotracheitis virus.

Bacteriophage phi6 nucleic acid was present as a torus after chromic acid-formaldehyde-OSO4 fixation and acetone and propylene oxide dehydration. A herpes virus, infectious bovine rhinotracheitis virus, had its DNA mostly as a torus, collapsed in the centre, or as a network, after glutaraldehyde-OSO4 fixation, but in an uncollapsed torus or network formation after chromic acid-formaldehyde-OSO4. This fixative stabilized nucleic acids, allowing acetone dehydration and plastic embedding without collapse of nucleic acid to the centre of the virion.

Chromium↗
PubMedDate not supplied

Role of aromatic amino acids in protein-nucleic acid recognition.

Statistical analysis of structures from the PBD has been used to examine the role that the aromatic amino acids play in protein-nucleic acid recognition. In protein-DNA complexes, the residues Phe and His are found to bind selectively to the DNA chain--Phe to A and T, and His to T and G. The preferred binding modes are identified, and the interactions involving Phe are shown to be important in the transcription process. In protein-RNA complexes, Phe is found to occur far less often and is instead replaced by Trp, which binds selectively to C and G, offering a possible mechanism for differentiation between the two nucleic acids. SASA analysis of the two sets of complexes suggests that all of the aromatic amino acids are more heavily involved in binding than would be expected on the balance of probability. Phe and Tyr occur approximately equal in both sets of data, whereas the proportions of His and Trp vary considerably, supporting the idea that these residues may be involved in differentiating between the two nucleic acids.

Amino Acids, Aromatic↗