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Review article (peer-reviewed)

Volume (Issue) 43(7)
Page(s) 974 - 984


The three-dimensional architecture and function of nucleic acids strongly depends, among other factors, on the presence of metal ions. Most importantly, metal ions, needed to compensate the negative charge of the phosphate-sugar backbone, allow and induce folding of complicated RNA structures. On the other hand, metal ions bind to specific sites to stabilize local motifs and to be positioned correctly to aid in, or even enable, the catalytic mechanism of, e.g., ribozymes. Many nucleic acids thereby exhibit large differences with regard to folding and activity based not only on the concentration but also on the nature of the metal ion applied. As a consequence, to understand the role of metal ions in nucleic acids, it is not only necessary to know the exact positioning and coordination sphere of each specifically bound metal ion, but also its intrinsic site affinity. However, the quantification of metal ion affinities to certain sites in a single-stranded (though folded) nucleic acid is a demanding task and only a few experimental data exist. In this Account we present a new tool to estimate the binding affinity of a given metal ion based on its coordinating and ligating sites within the nucleic acid: To this end we have summarized the available affinity constants of Mg2+, Ca2+, Mn2+, Cu2+, Zn2+, Cd2+ or Pb2+ for their binding to nucleobase residues, mono- and dinucleotides, and we have also estimated those of the phosphodiester bridge. In this way stability increments for each liganding site are obtained and a clear selectivity of the ligating atoms as well as their discrimination by different metal ions can thus be recognized. Based on these data we propose a concept that allows to estimate the intrinsic stabilities of nucleic acid-binding pockets for the mentioned metal ions. For example, the presence of a phosphate group has a much larger influence on the overall affinity of Mg2+, Ca2+, or Mn2+ compared to, e.g., Cd2+ or Zn2+. In the case of the latter two metal ions, the guanine N7 position is the strongest intrinsic binding site. By adding up the individual increments like building blocks, one receives an estimate not only for the overall stability of a given coordination sphere, but also for the most stable complex if an excess of ligating atoms is available in a binding pocket saturating the coordination sphere of the metal ion. Hence, the here described empirical concept of adding up known intrinsic stabilities, like building blocks, to an estimated overall stability will help to understand the accelerating or inhibiting effects of different metal ions in ribozymes and DNAzymes.