Nucleic Acid Base Pairs Research Articles

Thermodynamic Effect of Complementary Hydrogen Bond Base Pairing on Aromatic Stacking Interaction in the Guanine-X-Trp Complex (X=Adenine, Guanine, Cytosine, Thymin.

Four kinds of X-Trp (X=adenine, guanine, cytosine, thymine) were synthesized as model compounds to investigate the effect of complementary hydrogen bond base pairing on the stacking interaction of Trp with nucleic acid base. Association constants (Ka) of these compounds with two guanine derivatives (9-ethylguanine and 9-ethyl-7-methylguanine) were determined by Eadie-Hofstee plots of 1H-NMR titration experiments, and the thermodynamic parameters (ΔH, ΔS and ΔG) for the respective complexes were obtained by van't Hoff analyses based on the temperature dependence of the Ka values. The complexes were characterized by enthalpy/entropy compensations, where the interaction of cytosine-Trp with guanine derivatives was largely enthalpy-driven, accompanied by a small entropy component, whereas those of remaining complexes were all associated with a large increase in entropy, accompanied by a small positive enthalpy component. The present insight on the binding of X-Trp with a guanine base provides a thermodynamic basis for the importance of cooperative hydrogen bond pairing and aromatic stacking interactions in the specific recognition of a nucleic acid base pair by protein.

Laser Separation of Geometrical Isomers of Weakly Bound Molecular Complexes

Molecular assemblies held together by weak intermolecular bonds exhibit a rich variety of geometries. Even a simple complex formed by only two molecules can adopt several conformations corresponding to different geometrical isomers. Isomers of small polar dimers can be isolated nondestructively by taking advantage of a selective and reversible ionization process, with the use of a mass spectrometry method that allows the determination and control of the geometrical configuration of neutral or negatively charged molecular complexes in supersonic beams. Here, the method is applied to isolated nucleic acid base pairs that can be selected in stacked or H-bonded configurations.

Do C-H...O hydrogen bonds contribute to the stability of nucleic acid base pairs?

The possible formation of inter-base C-H.O hydrogen bonds in A.T, A.U and certain non-Watson-Crick base pairs is examined. A geometrical analysis in conjunction with implications for the thermodynamic stability of the base pairs suggests that C-H.O hydrogen bonds could form in nucleic acid base pairs. They may alleviate destabilizing interactions that would arise if an unsatisfied hydrogen-bond acceptor were present and mediate secondary hydrogen-bonding effects in these base pairs.

Hydrogen bonding motifs of protein side chains: descriptions of binding of arginine and amide groups.

The modes of hydrogen bonding of arginine, asparagine, and glutamine side chains and of urea have been examined in small-molecule crystal structures in the Cambridge Structural Database and in crystal structures of protein-nucleic acid and protein-protein complexes. Analysis of the hydrogen bonding patterns of each by graph-set theory shows three patterns of rings (R) with one or two hydrogen bond acceptors and two donors and with eight, nine, or six atoms in the ring, designated R2(2)(8), R2(2)(9), and R1(2)(6). These three patterns are found for arginine-like groups and for urea, whereas only the first two patterns R2(2)(8) and R2(2)(9) are found for asparagine- and glutamine-like groups. In each case, the entire system is planar within 0.7 A or less. On the other hand, in macromolecular crystal structures, the hydrogen bonding patterns in protein-nucleic acid complexes between the nucleic acid base and the protein are all R2(2)(9), whereas hydrogen bonding between Watson-Crick-like pairs of nucleic acid bases is R2(2)(8). These two hydrogen bonding arrangements [R2(2)(9)] and R2(2)(8)] are predetermined by the nature of the groups available for hydrogen bonding. The third motif identified, R1(2)(6), involves hydrogen bonds that are less linear than in the other two motifs and is found in proteins.

Synthesis and X-ray crystal structure of a novel tetrathiafulvalene dimethyl[2,4-dioxo(1H,3H)pyrimido]tetrathiafulvalene, able to form intermolecular hydrogen bonds of nucleic acid base-pair type

The efficient synthesis, molecular and crystal structure, chemical, spectroscopical and electrochemical properties and charge-transfer salts of dimethyl[2,4-dioxo(1H,3H)pyrimido]tetrathiafulvalene, a novel π-electron donor able to form intermolecular hydrogen bonds of nucleic acid base-pair type, are described.

Synthesis and Investigation of New Tetrathiafulvalenes Able to Form Intermolecular Hydrogen Bonds of the Nucleic Acids Base Pairs Type

Abstract The synthetic methods are worked out for preparing of 2,4-dioxopyrimido- and 2,4-aminooxopyrimidotetrathiafulvalenes. Redoxproperties and formation of charge transfer complexes and cation-radical salts are investigated. X-ray crystal structure confirm formation of dimers by means of hydrogen bonds.

Current potential of antisense oligonucleotides as therapeutic drugs

Antisense oligonucleotides have great potential as rationally designed therapeutic drugs by taking advantage of the basic Watson-Crick base pairing of nucleic acids. Such oligonucleotides may block synthesis of a specific protein, such a c-myb, and prevent smooth muscle proliferation involved in restenosis. Although promising, the technology has some major hurdles to overcome before fruition. These include obtaining a stable backbone that can enter cells readily, overcoming problems of chirality, and solving the problems of delivery and metabolism. Although there are many reports of successful experiments using antisense oligonucleotides, one must always keep in mind the complex nature of these experiments, as well as nonspecific effects that may masquerade as antisense effects.

Synthesis and Investigation of New Tetrathiafulvalenes Able to Form Intermolecular Hydrogen Bonds of the Nucleic Acids Base Pairs Type

Synthesis and Investigation of New Tetrathiafulvalenes Able to Form Intermolecular Hydrogen Bonds of the Nucleic Acids Base Pairs Type

Theoretical Studies on the Intercalation of Actinomycin between Nucleic Acid Base Pairs

Theoretical Studies on the Intercalation of Actinomycin between Nucleic Acid Base Pairs

What base pairings can occur in DNA? A distributed multipole study of the electrostatic interactions between normal and alkylated nucleic acid bases

Ab initio distributed multipole electrostatic calculations are used to predict likely nucleic acid base pair structures for both the gas phase and within a double helical backbone, as represented by simple constraints. The resulting structures are interpreted by comparison with an analysis of the experimental variation of base pair geometries found in oligonucleotide crystals. Our calculations on all pairs of the normal bases (G, A, T, C) correctly predict all the multiply hydrogen-bonded structures, in agreement with supermolecule SCF calculations, and also predict some new low-energy structures. Consideration of the helical constraints confirms that the Watson–Crick G · C and A · T pairings are most favourable for inclusion in DNA, but certain mismatch base pairs, G · T and G. · A, are also energetically favourable and their geometries correspond to the experimentally observed wobble conformations. This approach is also used to study the effect of the O6 methylation of guanine which can form a doubly hydrogen-bonded Watson–Crick-like structure with thymine. However, there are also a range of O6-methylguanine · cytosine structures which fit into the helical backbone and are energetically competitive. Thus the mutation-inducing effects of this base modification are likely to be very sensitive to the exact sequence and local conformation of the DNA.

分子設計に関する基礎研究と医薬化学への展開

A new concept of cyclic conjugation as a modification of the Huckel rule has proven to be useful as a general method for predicting thermal stabilities and electronic properties of unsaturated cyclic organic molecules. We have been applying this concept to the design of reagents such as p-benzoquinone, polyquinones, and 1, 4-dithiins. Our efforts for the molecular design have relied extensively on the use of pericyclic reactions as pivotal steps in the total synthesis of polycyclic natural products incorporating fused heterocyclic subunits, targets that traditionally have provided fertile grounds for the development of new synthetic strategies. In order to obtain a quantitative understanding of the linkage between drug-bioreceptor complex formation, we have investigated the design and synthesis for the biologically active compounds (receptor probes) as follows : 1) the design and structure-activity relationship of a series of S-activated opioid agonist and antagonist ligands, 2) the design and synthesis of crowned morphine as the opioid receptor probes and 1, 4-benzoquinones as ionophore-dienophile combined systems, 3) synthesis of the base stacking and hydrogen-bonded nucleic acid base pair.

Experimental and Theoretical Study of Energetics of Complex Formation Between Nucleic Acid Bases and the Bases with Amide Group

A number of nucleic acid base pairs and complexes between the bases and the amide group of acrylamide have been studied experimentally by using mass spectrometry and theoretically by the method of atom-atom potential function calculations. It has been found from temperature dependencies of peak intensities in mass spectra of m2.2.9(3) Gua.m1Ura, m9 Ade.m1Cyt, m2.2.9(3) Gua.m1Gua.m1Cyt pairs that enthalpy values, delta H, of the complex formation are equal to 14.2 +/- 1.1, 13.5 +/- 1.3 and 16.4 +/- 1.4 kcal/M, respectively, and those of acrylamide with m1.3(2) Ura and m1Thy corresponds to 9.7 +/- 1.0 and 6.8 +/- 0.6 kcal/M. There is a good agreement of the experimental data with calculations when taking into account both the amino-oxo and the amino-hydroxy tautomeric forms of guanine. A combined use of the data allows us to determine the energy, the modes of interaction and the structure of the complexes. The results are discussed in connection with the modelling of molecular structure of biopolymers by the method of classical potential functions, protein-nucleic acids recognition and fidelity of nucleic acids biosynthesis.

Interaction energy studies on antibiotics nucleoside analogs 2-azaadenine

The 2-azaadenine antibiotic is known to be a potent cytotoxic nucleoside analog. Evaluation of the interaction energy of this molecule with nucleic acid bases and base pairs has been performed using a quantum-mechanical perturbation technique. Both in-plane and stacking energies have been computed. These energy values along with their sites of association have been compared with the standard energy values and spatial positions for the nucleic acid bases during transcription. The results have been examined in the light of their biological significance.

Photon antennae assembled by nucleic acid base pairing

Photon antennae assembled by nucleic acid base pairing

Does hydrogen peroxide exist “free” in biological systems?

Hydrogen peroxide (H 2O 2) can diffuse far from the site of production to intracellular locations where biological effects may be greater. The diffusion range is extended by H 2O 2 carriers formed spontaneously by hydrogen bonding with monomeric and polymeric compounds, including amino and dicarboxylic acids, peptides, proteins, nucleic acid bases, and nucleosides. Hydrogen peroxide adducts (HPAs) are readily synthesized, e.g., crystalline histidine (His)-H 2O 2 adducts. An equilibrium exists between an adduct-forming compound and H 2O 2. The detection and relative stabilities of HPAs are measured by the degree of decomposition of H 2O 2 as influenced by test compounds in buffered solution competing with glucose or fructose for H 2O 2. The HPAs delay decomposition of H 2O 2 up to several hundredfold. The overall charge on an HPA, i.e., its ability to penetrate cell membranes, influences the cytotoxic and clastogenic effects of H 2O 2. Growth inhibition of Salmonella typhimurium LT 2 by H 2O 2 is enhanced by neutral HPAs but decreased by anionic HPAs. Addition of catalase 1, 10, or 30 min after inoculation of S. typhimurium LT 2 reduces or nearly eliminates partial growth inhibition by H 2O 2, but a neutral HPA, expecially his-H 2O 2, transported H 2O 2 into the cells within 1 min, and in about 10 min completely inhibited growth. The stability of HPAs decreases with increasing pH or increasing temperature, while added Fe(II) in the presence and absence of EDTA accelerates H 2O 2 and HPA decomposition. Calculations indicate H 2O 2 hydrogen bonds with nucleic acid-base pairs with no apparent bond strain and energy stabilization comparable to normal hydrogen bonding.

Ligation with T4 RNA ligase of an oligodeoxyribonucleotide to covalently-linked cross-sectional base-pair analogues of short, normal, and long dimensions

Compounds that are covalent analogues of nucleic acid base pairs of normal, long, and short C1' to C1' dimensions [B. Devadas and N.J. Leonard (1990) J. Am. Chem. Soc., 112, 3125-3135.] have been added to the oligodeoxyribonucleotide d(A)6 with bacteriophage T4 RNA ligase as a prelude to placing them at defined loci within nucleic acid duplexes. Analogue cross sections that represent a normal Watson-Crick base pair as well as a pyrimidine-pyrimidine and a purine-purine apposition were ligated in modest yields (approximately 20%) to the oligonucleotide. Ligation conditions were optimized for each analogue, and the cross section was joined to only a single oligonucleotide in each case. The structures of the ligated products were proved by HPLC, enzymatic degradation, and spectroscopic analyses.

Biological activity of an antibiotic puromycin—A theoretical study

Puromycin is known to be an anti-tumor agent. Evaluation of interaction energy of this molecule with nucleic acid bases and base pairs has been performed using quantum-mechanical perturbation technique. Both in-plane and stacking energies have been evaluated. These energy values along with their sites of association have been compared with the standard values during transcription process. The results have been examined in the light of their biological significance.

Inhibition of murine monocyte proliferation by a colony-stimulating factor-1 antisense oligodeoxynucleotide. Evidence for autocrine regulation.

Using a combination of v-myc and v-ras oncogenes, we have established a growth factor-independent monocyte cell line from murine fetal liver (FL-ras/myc). Biologic and molecular characterization demonstrated that the gene for the macrophage growth factor CSF-1 and the c-fms proto-oncogene (CSF-1 receptor) are expressed in this cell line, thus suggesting autocrine regulation as a possible mechanism for the unregulated growth of these cells. To study this possibility, we used 1) mAb, to neutralize the CSF-1 protein produced by the cell line, and 2) antisense oligomers, to inhibit CSF-1 gene products by specific base-pairing of complementary nucleic acids. We report here that both approaches inhibited in vitro cell growth by 60 to 70%, whereas the combination of oligomer and mAb inhibited proliferation by 95%. However, control antisense oligomers (50% bp mismatch with CSF-1 mRNA) did not inhibit FL-ras/myc cell growth. Furthermore, the inhibitory effects of mAb and oligomers were reversible when they were removed from the media. Detection of cell-associated CSF-1 protein by immunofluorescence showed that cells treated with the antisense oligomer expressed significantly less CSF-1 protein. These results indicate that the FL-ras/myc cell line requires CSF-1 for autonomous growth and that oligomers can efficiently block production of autocrine growth factors.

The influence of Li+, Na+, Mg2+, Ca2+, and Zn2+ ions on the hydrogen bonds of the Watson–Crick base pairs

The interaction of mono- and divalent metal ions with the nucleic acid base pairs A:T and G:C has been studied using ab initio self-consistent field Hartree-Fock computations with minimal basis sets. Energy-optimized structures of the two base pairs with a final base-base distance of L = 10.35 A have been determined and were further used in calculations on ternary complexes Mn+ - A:B together with previously computed coordination geometries of the cations at adenine (Ade), thymine (Thy), and guanine (Gua). Besides the binding energy of the various metal ions to the base pairs, changes in the stability of the H bonds between Ade and Thy or Gua and Cyt have been determined. Polarization effects of the metal ion on the ligand turned out to increase the binding between complementary bases. Regardless of the metal species, cation binding to Gua N(3) and Thy O(2) leads to a special increase in H-bond stability, whereas binding to Ade N(3) changes the H-bond stability least. Situated in between are the stabilizing effects caused by Gua and Ade N(7) coordination. A remarkable relation between the stability of the H bond and the distance from metal binding site to H bonds was found. This relationship has been rationalized in terms of partial charges of the atoms participating in H bonding, which can reveal the trend in the electrostatic part of total H bond energy. It can be shown that a short distance between coordination site and acceptor hydrogen increases the H-bond strength substantially, while a long distance shows minor effects as supposed. On the other hand, the opposite effect is observed for the influence of the distance between binding site and donor atom. A comparison of our findings with a new model of transition metal ion facilitated rewinding of denatured DNA proposed by S. Miller, D. VanDerveer, and L. Marzilli is given [(1985) J. Am. Chem. Soc. 107, 1048-1055].

Molecular-orbital study of the relative stability of protonated nucleic acid base pairs

Molecular-orbital MNDO/M calculations of various purine-pyrimidine complexes were carried out to study the effect of nucleic acid base protonation on the relative stability of their complementary and non-complementary pairs. The protonation of one of the bases was shown to produce considerable changes in the formation energy and structure of these complexes. The protonation of the 06, N3 and N7 atoms in guanine increases the relative stability of their complementary pair, whereas the protonation of N3 or N7 of adenine and O2 or O4 of uracil decreases the energy difference for the formation of matched and mismatched complexes. Very high stability was observed for the non-complementary pair A (N1) +C, in which adenine is protonated at the N1 site, and the mismatched pair AC + (O2).