Metal Ion Binding to Nucleic Acids

1. Metal Ion Binding to Nucleic Acids Typical modes of metal ion binding 1. phosphates 2. bases 3. intercalation Binding to either the phosphate groups or by intercalation is typically non-specific; i.e., it does not depend on a particular base sequence Binding to the bases will depend on the type of bases that are present

2. Nucleotide structures Nucleosides are composed of a ribose or deoxyribose sugar, and a heterocyclic base Nucleosides (RNA) Deoxynucleosides (DNA) Nucleotides (and deoxynucleotides) are nucleosides that contain one or more phosphate groups

3. Metal Binding Sites Purines - adenosine and guanosine Pyrimidines - cytidine and uridine

4. Metal-adenine complexes Co(II)-adenine Cu(II)-adenine In each case N9 plays the major role in metal ion binding However, in nucleosides and nucleotides this position is blocked by a glycosidic bond to ribose

5. Metal-methyladenine complexes Cu(II)-9-methyladenine Pt(II)-9-methyladenine Blocking N9 leads to metal ion coordination at the next best site - N7

6. Mo-adenine complex Mo(II)-9-ethyladenine Mo also coordinates to N7 (as well as N6) and forms the typical bridged complex to an adjacent Mo

7. Metal-nucleoside complex Cu(II)-(glygly)cytidine Binding Cu to a dipeptide model compound allows only a single ligand position to interact at the N3 position of a pyrimidine nucleoside

8. Preferred Bidentate Coordination Sites There are a number of potential bidentate sites for metal ion coordination The preferred sites depends on the metal ions involved possible sites

9. Metal-nucleotide complex Co(II)-inosine monophosphate Co(II) directly coordinates to the N7 position The metal bound waters form hydrogen bonds to the exocyclic oxygen (O6) and the phosphate group

10. RNA (& DNA) structures Where can metal ions interact in these nucleic acid polymers?

11. DNA Duplex Structures DNA is typically found in a double stranded helix However, there are three different types of helices Of these, the B form of DNA is the most common helix This B-helix has a wide or major groove and a narrow or minor groove Intercalation can occur in either of these grooves, but binding to the major groove is preferred

12. Metal-DNA intercalation complexes Compounds that bind to duplex DNA by intercalation tend to be flat, planar structures metal complexes that intercalate in the major groove metal complexes that intercalate in the minor groove

13. DNA bindingRu(II)-complexes Promotes double-stranded cleavages at cruciform sites by photoactivation A photoactivated probe for the A helix form of DNA Targets binding in the major groove of the B form of DNA

14. Cu(II)-DNA Cleavage Binding of a DNA-cleaving peptide to double stranded DNA

15. Metal Sites on tRNA Red dots represent the most likely metal ion binding sites on transfer-RNAs Many of these sites are located at loops and turns where the metal ions can interact with multiple potential donor atoms

16. Mg(II)-yeast tRNA As an example, Mg(II) binds at a crossover point between two loops in a yeast tRNA There is only one direct interaction between Mg(II) and a backbone phosphate oxygen However, Mg-coordinated waters form hydrogen bonds to donor atoms from three different bases

17. Cis-Pt DNA structure Cis-dichloroplatinum is a very potent antitumor drug Its mode of action is to bind to specific regions of DNA causing distortions in the DNA duplex that prevents replication

18. Cis-Pt dinucleotide complex The major complex that forms with cis-Pt is an intrastrand crosslink between adjacent G-G or A-G bases The chloro ligands on cis-Pt are displaced by waters as the drug is administered These cis-waters are then replaced by the N7 nitrogens from adjacent nucleotide bases

19. Metal intercalation complexes Intercalation involves insertion of a complex between successive base pairs in duplex DNA In order to bind by intercalation a complex must contain a planar ligand Two of these ligands will intercalate into duplex DNA Which two ? Ethidium bromide is a known intercalator into DNA Upon binding it causes a shift in the gel mobility of double stranded DNA This same pattern is observed with two of the Pt complexes However, the pyridine rings do not remain planar in the first complex and therefore prevents DNA intercalation

20. Metal intercalation complexes While planar rings in metal complexes can intercalate into DNA, if the metal ion is tethered through a spacer group then the metal may not be inserted between the base pairs upon binding In these cases intercalation positions the metal ion to induce DNA strand cleavage If specificity can be introduced into the intercalating ligand then selective DNA strand cleavage will result

21. Chiral metal complex with DNA The presence of methyl groups on phenanthroline prevents DNA intercalation However, this chiral metal complex will preferentially bind to the A form of DNA In the presence of oxygen this complex can be photoactivated for DNA cleavage

22. Summary • Metal ions can interact with many potential donor atoms in nucleotides • Nucleic acid binding involves interactions with phosphates and bases as well as intercalation between bases • Small metal complexes have been designed to target different DNA structures • cis-Pt drugs crosslink DNA to prevent duplication in rapidly replicating tumor cells • Several types of intercalating complexes can be photoactivated to cause selective DNA cleavages