Metal ions nucleic acid structures

X-ray crystallographic analyses usually provide structural information that correctly represents the actual structures of metal ion-nucleic acid complexes in the crystal this usually represents an environment that is drastically different from normal solution conditions. Obviously, such analyses are limited to complexes that are both stable and amenable to crystallization. In comparison, solution NMR spectroscopy data are much more generally applicable to the analysis of metal ion-nucleic acid structure, " " but can be more easily misinterpreted owing to factors such as the distribution of metal ions among several binding sites and the intrinsically weaker nature of some of the interactions that are studied. Also, nucleic acid crystallization requires the formation of ordered and uniform intermolecular interactions between nucleic acids. These intermolecular interactions may either compete or interfere with the formation of certain metal-nucleic complexes and promote the formation of unnatural metal binding centers. ... 

Interactions of the same water molecules with RNA nucleotides (via H-bonding) and metal ions (via inner-sphere coordination) could stabilize specific metal ion-nucleic acid complexes (e.g. in Mg + -tRNA chelates) and also create the possibility for direct proton transfer through a water chain that could play a role in ribozyme-metal ion catalysis and in the mechanism of metal-dependent nucleases and polymerases. Similar types of H-bonds between different nucleotide residues have been found in tRNA tertiary structures, where they provide additional stabilization of tertiary interactions. 

This article does not attempt to be comprehensive, but rather presents selected examples to illustrate key facets of metal ion-nucleic acid interaction. The focus is on the chemical and structural properties of nucleic acids and metal ions relevant to their interactions, and in illustrating that both contribute as equal partners to the complexity of their interactions. 

As already noted, metal ions play a vital role in DNA tetraplex structures. The first MD study that did address this point was published in 1994. It was found that the simulation could reproduce a few properties of the structure but could not correctly describe the metal ion nucleic acid interaction. This is not surprising as at that time the particle-mesh Ewald roach was not yet available. Later simulations do not suffer from this deficioicy. 

L. G. Marzilli, T. J. Kistenmacher, and G. L. Eichhom Structural Principles of Metal Ion—Nucleotide and Metal Ion—Nucleic Acid Interactions (Reference 8, pp. 179— 250). 

The foundation of metal ion and nucleic acid interactions as a chemotherapy originate with the well known work of Rosenberg64 on platinum(II) complexes. Those containing chelating agents could destabilize nucleic acid structures by removing cations which promote the stability of histones. 

Polynucleotide polymerases, or nucleotidyl transferases, are enzymes that catalyze the template-instructed polymerization of deoxyribo- or ribonu-cleoside triphosphates into polymeric nucleic acid - DNA or RNA. Depending on their substrate specificity, polymerases are classed as RNA- or DNA-dependent polymerases which copy their templates into RNA or DNA (all combinations of substrates are possible). Polymerization, or nucleotidyl transfer, involves formation of a phosphodiester bond that results from nucleophilic attack of the 3 -OH of primer-template on the a-phosphate group of the incoming nucleoside triphosphate. Although substantial diversity of sequence and function is observed for natural polymerases, there is evidence that many employ the same mechanism for DNA or RNA synthesis. On the basis of the crystal structures of polymerase replication complexes, a two-metal-ion mechanism of nucleotide addition was proposed [1] during this two divalent metal ions stabilize the structure and charge of the expected pentacovalent transition state (Figure B.16.1). 

Just as metal ions can bind nucleic acids both specifically and nonspecifically, they can promote both specific and nonspecific cleavage of nucleic acids. The rate and specificity of the cleavage reactions varies markedly with the identity of both metal ions and nucleic acid structures, as well as with the couditions of experimeuts. Higher pH, temperature, and concentrations of metal ions could enhance the rate of the polynucleotide cleavage but would decrease the specificity. 

Transition metal ion incorporation in hybrid inorganic-nucleic acid structures adds another dimension to the field of DNA nanotechnology because metal ions, in particular those with unpaired d electrons, have a broad range of electronic and magnetic properties. In most applications in material science, DNA is used as a scaffold for uniform binding of metal ions either to nucleobases or to ligands attached to nucleobases. For example, Braun et al. 

The rich coordination chemistry of transition metal ions has been used not only to create metal-ligand complexes that play the role of alternative nucleo-base pairs within nucleic acid duplexes, but also to influence the secondary structure adopted by the nucleic acid, for example, hairpin, duplex, or triplex, and to create connectors for such nucleic acid structures. In this context, oligonucleotides that contain terminal ligands can lead to structures distinct from those accessible by using centrally-modified oligonucleotides, such as cyclic structures or hairpins (Fig. 3). 

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. 

Triple-helix formation by G-rich oligonucleotides is supported by Mg + but strongly inhibited by physiological concentrations of certain monovalent cations, especially K+, most likely due to oligonucleotide self-association in competitive structures such as guanine-quadruplexes. Variation of the cation environment can differentially promote the assembly of multistranded nucleic acid structural alternatives. For example, by specifically counteracting the induction/stabilization of quadruplex structures by potassium ions, certain divalent ions (i.e. Mn +, Co +, and Ni + but not Mg +) at low millimolar concentrations allow triplex formation in the presence of 150mMK+. In contrast, certain mono- and divalent metal ions can promote the transition from Watson-Crick duplexes to G4 quadruplex structures relatively efficiently K+ > Ca + > Na+ > Mg + > Li+. ... 

The Eflfect of Metal Ions on the Structure of Nucleic Acids... 

More than half of all enzymes have metal ions in their structure these are metalloenzymes. In most cases, the metals are essential to the action of the enzyme and are often at the active site where the substrate for the biochemical reaction is bound. All organisms require certain trace elements for growth. Some of these trace elements are the metal ions that the organism incorporates into its metalloenzymes. Of the inorganic elements, the following have been found to be essential for some species of plant or animal Mg, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Mo, B, Si, Se, F, Br( ), and I. New elements are added to the list from time to time—titanium is a potential future candidate for inclusion, for example. In addition, Na, K, Ca, phosphate, sulfate, and chloride are required in bulk rather than trace amounts. Metal ions also play an important role in nucleic acid chemistry. The biochemistry of these elements is termed bioinorganic chemistry. ... 

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