Nucleic acids general discussion

Central to the quality of any computational smdy is the mathematical model used to relate the structure of a system to its energy. General details of the empirical force fields used in the study of biologically relevant molecules are covered in Chapter 2, and only particular information relevant to nucleic acids is discussed in this chapter. 

Once a target-based approach is embarked upon, the choice of target is the first step. In biological systems, there are generally four types of macromolecules that can interact with druglike molecules proteins, polysaccharides, lipids, and nucleic acids. As discussed in Chapter... 

We ll see later in this chapter and again in Chapter 29 that carbonyl condensation reactions occur frequently in metabolic pathways. In fact, almost all classes of biomolecules—carbohydrates, lipids, proteins, nucleic acids, and many others—are biosynthesized through pathways that involve carbonyl condensation reactions. As with the or-substitution reaction discussed in the previous chapter, the great value of carbonyl condensations is that they are one of the few general methods for forming carbon-carbon bonds, thereby making it possible to build larger molecules from smaller precursors. We ll see how and why these reactions occur in this chapter. 

To understand the extraordinary potential for DNA to be utilized as a material in construction processes, the general properties of this biomolecule will first be discussed. In addition, examples of naturally occurring nucleic acid-based nanostructures will be described that are of great importance both for cellular processes and conventional applications in molecular biotechnology. 

Numerous organisms, both marine and terrestrial, produce protein toxins. These are typically relatively small, and rich in disulfide crosslinks. Since they are often difficult to crystallize, relatively few structures from this class of proteins are known. In the past five years two dimensional NMR methods have developed to the point where they can be used to determine the solution structures of small proteins and nucleic acids. We have analyzed the structures of toxins II and III of RadiarUhus paumotensis using this approach. We find that the dominant structure is )9-sheet, with the strands connected by loops of irregular structure. Most of the residues which have been determined to be important for toxicity are contained in one of the loops. The general methods used for structure analysis will be described, and the structures of the toxins RpII and RpIII will be discussed and compared with homologous toxins from other anemone species. 

In today s discussion of the origin of life, the RNA World (Chapter 6) is seen as much more important, and is much better publicized, than the protein world . However, nucleic acids and proteins are of equal importance for the vital metabolic functions in today s life forms. Peptides and proteins are constructed from the same building blocks (monomers), the aminocarboxylic acids (generally known simply as amino acids). The way in which the monomers are linked, the peptide bond, is the same in peptides and proteins. While peptides consist of only a few amino acids (or to be more exact, amino acid residues), proteins can contain many hundreds. The term protein (after the Greek proteuein, to be the first) was coined by Berzelius in 1838. 

A detailed discussion of the modes of occurrence and biological importance of the polynucleotides is outside the scope of this article. However, in examining the structures of polynucleotides, it is necessary to take into consideration the origins of the materials studied. The pioneer researches of Caspersson114 indicated that deoxyribonucleic acids are present exclusively in the nucleus, whereas ribonucleic acids are found chiefly in the cytoplasm and only to a small extent in the nucleus. This general outline of the distribution of nucleic acids within the cell has been confirmed and extended by more recent work,116 and it has been possible to isolate both types of nucleic acid from different cellular fractions of the same tissue.116... 

Values found for the molecular weight of deoxyribonucleic acids also vary considerably, but probably lie between 1.0 X 106 and 4.4 X 106. Various difficulties encountered in making such measurements have been discussed by Jordan,244 and it is probable that more reliable information will be obtained only when the behavior of polyelectrolytes in general is better understood. Certain of the techniques used are useful in detecting differences between different nucleic-acid preparations, but the discrepancies between the values given by different methods of measurement appear to vary with the degree of polymerization.246... 

Abstract This chapter updates but mostly supplements the author s Ange-wandte Review,111 setting in context recent advances based on protein and nucleic acid engineering. Systems qualify as a true enzyme mimics if there is experimental evidence for both the initial binding interaction and catalysis with turnover, generally in the shape of saturation kinetics. They are discussed under five broad headings mimics based on natural enzymes, on other proteins, on other biopolymers, on synthetic macromolecules and on small-molecule host-guest interactions. 

Gel electrophoresis is widely used in the routine analysis and separation of many well-known biopolymers such as proteins or nucleic acids. Little has been reported concerning the use of this methodology for the analysis of synthetic polymers, undoubtedly since in many cases these polymers are not soluble in aqueous solution - a medium normally used for electrophoresis. Even for those water-soluble synthetic polymers, the broad molecular weight dispersities usually associated with traditional polymers generally preclude the use of electrophoretic methods. Dendrimers, however, especially those constructed using semi-controlled or controlled structure synthesis (Chapters 8 and 9), possess narrow molecular weight distribution and those that are sufficiently water solubile, usually are ideal analytes for electrophoretic methods. More specifically, poly(amidoamine) (PAMAM) and related dendrimers have been proven amendable to gel electrophoresis, as will be discussed in this chapter. 

The concept of the similarity of molecules has important ramifications for physical, chemical, and biological systems. Grunwald (7) has recently pointed out the constraints of molecular similarity on linear free energy relations and observed that Their accuracy depends upon the quality of the molecular similarity. The use of quantitative structure-activity relationships (2-6) is based on the assumption that similar molecules have similar properties. Herein we present a general and rigorous definition of molecular structural similarity. Previous research in this field has usually been concerned with sequence comparisons of macromolecules, primarily proteins and nucleic acids (7-9). In addition, there have appeared a number of ad hoc definitions of molecular similarity (10-15), many of which are subsumed in the present work. Difficulties associated with attempting to obtain precise numerical indices for qualitative molecular structural concepts have already been extensively discussed in the literature and will not be reviewed here. 

The specific processes discussed above are all special cases of the general process (9.2.1). In all of these cases we have seen the explicit modification of the equilibrium constant of the corresponding process. As indicated in Eq. (9.2.3), the general modification requires knowledge of the solvation Gibbs energies of all the components involved in the process. For macromolecules such as proteins or nucleic acid, none of these is known, however. Nevertheless, some specific solvation effects are examined in Sections 9.4 and 9.5. 

Despite all the hype, it is important to note that, by mid-2002 at least, only a single nucleic acid-based product has been approved for medical use (an antisense-based product, discussed later). No gene therapy-based product had been approved for general medical use by that time. 

As in the case of protein structure (Chapter 4), it is sometimes useful to describe nucleic acid structure in terms of hierarchical levels of complexity (primary, secondary, tertiary). The primary structure of a nucleic acid is its covalent structure and nucleotide sequence. Any regular, stable structure taken up by some or all of the nucleotides in a nucleic acid can be referred to as secondary structure. All structures considered in the remainder of this chapter fall under the heading of secondary structure. The complex folding of large chromosomes within eukaryotic chromatin and bacterial nucleoids is generally considered tertiary structure this is discussed in Chapter 24. 

The majority of antiviral drugs which are under clinical development today generally interrupt viral nucleic acid synthesis. These compounds often do not affect host cell metabolism and possess considerable selectivity against virus-induced enzymes. This article discusses agents exhibiting significant antiviral activity against viral infections in animal model systems. 

The test depends on the 2-desoxyribose component of the nucleic acid and in experiments directed towards the synthesis of this sugar and its derivatives, the diphenylamine reaction has been used to obtain indications of the formation of the required product. Originally it was claimed that the test was specific for 2-desoxyribose but more recent investigations by Stacey and his coworkers48 have shown that the test is given by 2-desoxypentoses generally. Moreover, these workers have elucidated in part the mechanism of the test.48 These studies will be discussed more fully subsequently. 

While no examples of automated solid-phase oligosaccharide synthesis had been reported until the work described here,2 automated oligosaccharide synthesis was predated by efficient methods for the synthesis of peptides3 and nucleic acids.4 Here we briefly discuss the general features of each method, with particular emphasis on the scale and efficiency of peptide and nucleic acid synthesis. 

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