Metal with polynucleotides, interaction

G. L. Eichhom and Y. A. Shin, Interaction of metal ions with polynucleotides and related compounds. 

Figure 27-13 Proposed mechanism and transition state structure for the synthetic nucleotidyltransfer activity of DNA polymerase 3 (and other DNA polymerases). The chain-terminating inhibitor dideoxy CTP is reacting with the 3 -OH group of a growing polynucleotide primer chain. This -OH group (as -0 ) makes an in-line nucleophilic attack on Pa of the dideoxy-CTP. Notice the two metal ions, which interact with the phospho groups and which are held by three aspartate side chains. Two of the latter, Asp 190 and Asp 256, are present in similar positions in all of the polymerases. The active centers for the hydrolytic 3 -5 and 5 -3 exonuclease activities of some of the polymerases also appear to involve two-metal catalysis and in-line displacement. See Sawaya et al.27i...

Interactions of Transition Metal Ions with Polynucleotides. 55... 

In the following chapters the complex reaction of metals with macromolecules is discussed separately for each metal ion. To conclude this series an attempt will be made to correlate metal-polynucleotide interactions with biochemical pathways. 

Butzow, J. J., and G. L. Eichhorn Interactions of metal ions with polynucleotides and related compounds. IV Degradation of polyribonucleotides by zinc and other divalent metal ions. Biopolymers 3, 97 (1965). 

Why would people be interested in metal-nucleic acid interactions Perhaps because life as we know it is dependent on these interactions. Nucleic acids (DNA and RNA) are actually salts (or complexes) of metal ions from a chemical point of view. Therefore, it is difficult, if not impossible, to separate the behavior of DNA and RNA from their interactions with metal ions. We must also take into account specifically bound water molecules since they frequently mediate interactions between polynucleotides and metal ions. ... 

The Interaction of Metal Ions with Polynucleotides and Related Compounds... 

In this chapter we first summarize the basics needed to consider the interactions of metal ions and complexes with nucleic acids. What are the structures of nucleic acids What is the basic repertoire of modes of association and chemical reactions that occur between coordination complexes and polynucleotides We then consider in some detail the interaction of a simple family of coordination complexes, the tris(phenanthroline) metal complexes, with DNA and RNA to illustrate the techniques, questions, and applications of metal/nucleic-acid chemistry that are currently being explored. In this section, the focus on tris(phenanthroline) complexes serves as a springboard to compare and contrast studies of other, more intricately designed transition-metal complexes (in the next section) with nucleic acids. Last we consider how Nature uses metal ions and complexes in carrying out nucleic-acid chemistry. Here the principles, techniques, and fundamental coordination chemistry of metals with nucleic acids provide the foundation for our current understanding of how these fascinating and complex bioinorganic systems may function. 

It is necessary now to classify the metals with regard to their function in biological systems metals as cofactors of proteins, metalloen2ymes, communicative functions of metals, interaction of metal ions with polynucleotides, biometal-organic chemistry (e.g. metals in medicine). 

One of the most important aspects of the interaction between metals and polynucleotides is that which leads to compactness of structure in the polynucleotides. As polyions, they exhibit structures in solution which are strongly dependent on the concentration and valence of the cations (typically, the compact native structures are favoured by high salt concentrations and particularly by bivalent ions), but even with the transfer RNAs (among the most widely studied nucleic acids and despite analysis of the X-ray structures) the role and location of bound bivalent cations are uncertain. Leroy et al. have used various physical techniques to explore the structure of the central region in a couple of tRNAs from E. coli and thereby obtain evidence on the binding of Mn + and other metal ions. Their interpretation is that simple manganese-phosphate binding is supplemented by electrostatic interaction with distant phosphates. 

The reactivity of metal ions is not always the same with DNA and RNA. One reaction that is exclusive to RNA is depolymerization of the polynucleotide structure by the cleavage of the phosphodiester bonds. This depolymerization reaction, as with other RNA hydrolyses, can be induced by metal hydroxides, Zn being one of the most effective. A simple mechanism is that the Zn" chelates to the phosphate group and the 2 -hydroxyl group of ribose (the 2 -group is absent in DNA). Electron withdrawal by the Zn ion then weakens the phosphodiester linkage. Such a mechanism, however, does not take into account the observed influence of the nature of the adjacent base and the formation of metal-dependent products. Pb is also an effective catalyst in site-specific depolymerization of tRNA. In this case the metal has been shown to bind to the bases with only weak interactions with phosphate groups. The catalytic action has been interpreted in terms of nucleophilic attack by a metal-bonded hydroxide ion.134 This may have implications for the mechanisms of other metal ions active in this reaction. 

One may draw an analogy between nucleic acids and helicates, with on one side the polynucleotide strands and their interaction through hydrogen bonding and on the other side the oligobipyridine strands and their binding together via metal ion coordination. 

In the previous chapters the reactivity of metal ions with the monomer units of nucleic acids has been discussed. This section will deal with the binding of transition metals to the polynucleotides. There are also three types of complexes to be expected the metal-ring, the intermediate and the metal chain complex. The effect of the ribose or deoxyribose residue on the stability constants can be neglected since the reactivity of these sugars with cations is extremely low. However, as it will be seen later, the hydrolysis of polyribonucleotides is markedly facilitated by interaction of metal ions with the 2 —OH groups of the ribose. 

An interaction of metal ions with phosphates usually leads to stabilization of polynucleotide secondary and tertiary stmctures, depending on the metal ions and their concentrations, whereas base binding or chelating base and phosphate by the same metal ion may result in destabilization, conformational change, or denaturation of the polynucleotide structures (see also Sections 3.3.1 and 3.3.2). However, phosphate-specific binding can also induce significant conformational changes in DNA structure. The mechanisms of the latter structural interconversions are... 

Now we may examine in detail the interaction of one class of metal complexes with nucleic acids, how these complexes bind to polynucleotides, the techniques used to explore these binding interactions, and various applications of the complexes to probe biological structure and function. Tris(phenanthroline) metal complexes represent quite simple, well-defined examples of coordination complexes that associate with nucleic acids. Their examination should offer a useful illustration of the range of binding modes, reactivity, techniques for study, and applications that are currently being exploited and explored. In addition, we may contrast these interactions with those of other transition-metal complexes, both derivatives of the tris(phenanthroline) family and also some complexes that differ substantially in structure or reactivity. 

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