Transition metal complexes have captured considerable attention in the biomedical community because of their ability to bind certain nucleic acid structures and to promote chemical modification at or near the site of binding. Such processes occur """"""""naturally"""""""" when metalloproteins operate on DNA or RNA, when metal-based toxins or drugs select genetic material as their target, and when metal complexes are used as conformation specific probes of nucleic acids. These laboratories have recently identified a series of nickel complexes to be exceptional probes for the secondary and tertiary structure of guanine in DNA and RNA. The utility and application of these complexes will now be explored in depth using well defined models and large polynucleotide systems of current interest. An accurate description of nucleic acid folding must include a wide variety of conformations that significantly depart from the canonical double helix. Great interest in studying the polymorphic nature of nucleic acids has arisen from the preeminent role secondary and tertiary structure seems to play in recognition, regulation and reactivity of genetic information. While small oligonucleotide models may be examined in great detail by physical methods, larger systems may only be characterized through their chemical and biological activity. Ideally, reagents should be made available to identify the solvent accessibility of each group or site in a polynucleotide structure. Initial analysis suggests that the nickel complexes described herein are unrivaled in their absolute specificity for detecting guanine residues held in one of a number of non- Watson-Crick base pairing arrangements. Investigations will fully define the nickel reagent's selectivity with targets containing mismatched, bulged, hairpin and pseudoknot sequences. Oligonucleotide models have been chosen for these analyses so that direct correlations can be drawn between these chemical studies and the existing structural results obtained from magnetic resonance and crystallography. Polynucleotide studies will follow to provide a new perspective on key structures such as bends, cruciforms and protein-DNA complexes. Most importantly, the nickel species will also be applied to a number of contemporary problems of enormous impact. For example, the accessibility of guanine will be determined for RNA folding patterns that (i) regulate gene translation and (ii) form RNA-based catalysts.
