Nucleic backbone

Almost all of the calculations on polyads were performed for isolated base complexes thus neglecting effects of nucleic backbone, solvent and also of entropic contributions. Erqreriments most directly related to quantum-chemical results are gas phase investigations on base pairs.Nevertheless, it makes also sense to compare the results of quantum-chemical studies on base pairs or polyads to complete three-dimensional nucleic acid structures. One should realize, however, that there is a long way to go from results of quantum-chemical studies on building blocks to nucleic acid structure and function. The power of this approach is that it can help to separate the effects of different parts of the nucleic acid, such as backbone and bases, on the overall structure. In addition, it provides useful information on charge distribution and electrostatic potentials relevant for the determination of interaction sites with cations such as K, the most abundant cation in cells. Finally, the interaction energies can be studied in great detail. For example non-additive contributions can be determined. 

The visuahzation of hundreds or thousands of connected atoms, which are found in biological macromolecules, is no longer reasonable with the molecular models described above because too much detail would be shown. First of aU the models become vague if there are more than a few himdied atoms. This problem can be solved with some simplified models, which serve primarily to represent the secondary structure of the protein or nucleic acid backbone [201]. (Compare the balls and sticks model (Figure 2-124a) and the backbone representation (Figure 2-124b) of lysozyme.)... 

En me Mechanism. Staphylococcal nuclease (SNase) accelerates the hydrolysis of phosphodiester bonds in nucleic acids (qv) some 10 -fold over the uncatalyzed rate (r93 and references therein). Mutagenesis studies in which Glu43 has been replaced by Asp or Gin have shown Glu to be important for high catalytic activity. The enzyme mechanism is thought to involve base catalysis in which Glu43 acts as a general base and activates a water molecule that attacks the phosphodiester backbone of DNA. To study this mechanistic possibiUty further, Glu was replaced by two unnatural amino acids. 

Most reactions of nucleic acid hydrolysis break bonds in the polynucleotide backbone. Such reactions are important because they can be used to manipulate these polymeric molecules. For example, hydrolysis of polynucleotides generates smaller fragments whose nucleotide sequence can be more easily determined. 

Epoxides are often encountered in nature, both as intermediates in key biosynthetic pathways and as secondary metabolites. The selective epoxidation of squa-lene, resulting in 2,3-squalene oxide, for example, is the prelude to the remarkable olefin oligomerization cascade that creates the steroid nucleus [7]. Tetrahydrodiols, the ultimate products of metabolism of polycyclic aromatic hydrocarbons, bind to the nucleic acids of mammalian cells and are implicated in carcinogenesis [8], In organic synthesis, epoxides are invaluable building blocks for introduction of diverse functionality into the hydrocarbon backbone in a 1,2-fashion. It is therefore not surprising that chemistry of epoxides has received much attention [9]. 

Fig. 1 Chemical structures of backbone modifications used in therapeutic nucleic acid analogs. Shown are the unmodified DNA/RNA chemical structures in addition to a selection of first (PS), second (OMe, MOE), and third generation (PNA, LNA, MF) nucleic acid modifications...

The development of the aminoethylglycine polyamide (peptide) backbone oligomer with pendant nucleobases linked to the glycine nitrogen via an acetyl bridge now often referred to by PNA (peptide nucleic acid Fig. 4.1), was inspired... 

Nielsen P.E., Haaima G. Peptide nucleic acid (PNA). A DNA mimic with a pseudopeptide backbone. Chem. Soc. Rev. 

Nielsen P.E., Egholm M., Berg R. H., Buchardt O. Peptide nucleic acids (PNA) oligonucleotide analogs with a polyamide backbone. In Antisense Research and Applications. Crooke S.T., Le-BLBu B. (Eds). CRC Press, Boca Raton,... 

The amino acid sequence of our first aPNA (which we termed backbone 1 or bl) was designed based on this amphipathic hehx sequence (Fig. 5.3 B). Specifically, this aPNA backbone included hydrophobic amino acids (Ala and Aib), internal salt bridges (Glu-(aa)3-Lys-(aa)3-Glu), a macrodipole (Asp-(aa)i5-Lys), and an N-ace-tyl cap to favor a-helix formation. The C-termini of these aPNA modules end in a carboxamide function to preclude any potential intramolecular end effects. Each aPNA module incorporates five nucleobases for Watson-Crick base pairing to a target nucleic acid sequence. 

These studies showed thaL in the absence of nucleic acid, the backbone 1 aPNA had significant a-hehcal content at pH 7 whereas the backbone 2 aPNA was largely in a random coil conformation at physiological pH. The latter aPNA did become a-helical at higher pHs in a manner reminiscent of the structurally related amphipathic peptides. 

A nucleic acid polymer contains nucleotide chains in which the phosphate group of one nucleotide links to the sugar ring of a second. The resulting backbone is an alternating sequence of sugars and phosphates, as shown in... 

Classical gene transfer methods still in use today are diethylamino ethyl (DEAE)-dextran and calcium phosphate precipitation, electroporation, and microinjection. Introduced in 1965, DEAE-dextran transfection is one of the oldest gene transfer techniques [2]. It is based on the interaction of positive charges on the DEAE-dextran molecule with the negatively charged backbone of nucleic acids. The DNA-DEAE-dextran complexes appear to adsorb onto cell surfaces and be taken up by endocytosis. 

Three classes of nucleic acid triple helices have been described for oligonucleotides containing only natural units. They differ according to the base sequences and the relative orientation of the phosphate-deoxyribose backbone of the third strand. All the three classes involve Hoogsteen or reverse Hoogsteen-like hydrogen bonding interaction between the triple helix form-... 

Along with stomach, bile, and lactic acids, there are many other acids in the human body These include, but are not limited to, nucleic acids, amino acids, fatty acids, and vitamins such as folic and ascorbic acids. Nucleic acids, including RNA (ribonucleic acid) and DNA (deoxyribonucleic acid), are long chains of phosphates and sugar to which nucleotide bases are attached. The phosphate molecules in the backbone of RNA and DNA are derived from phosphoric acid. Therefore, DNA is very weakly acidic. 

P2j Z = 2 DX = 1.43 R = 0.067 for 1269 intensities. The uracil residue is in the anti (63.4°) disposition. The conformation of the D-ribosyl group is 2T3 (176.8°, 37.5°). The orientation about the exocyclic, C-4 -C-5 bond is t (—174.2°). The phenyl and uracil ringsofthe same molecule lie in almost parallel planes, 120 pm apart. The phenyl group is disordered. The uracil ring is sandwiched by the phenyl rings, and vice versa. The 0-1 and N-a atoms of the peptide backbone are hydrogen-bonded to 0-4 and N-3 of atranslationally related uracil to form cyclic dimers. Such interactions serve as models for nucleic acid-protein interactions. [Coordinate errors H(02 ) x should be —1574, instead of —1474 H(Na)2 z should be —145 instead of— 645.]... 

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