Probing the stacking properties of nucleosides and nucleotides with heteroaromatic amines and the effect of metal ion-bridging on the stability of the stacks. Implications for biological systems

Abstract

Noncovalent interactions play important roles in modern chem. research encompassing also bio- systems. Among these interactions arom.-ring stacking is esp. pronounced as, next to hydrogen bonding, hydrophobic and ionic interactions, it is crucial for the three-dimensional structure of nucleic acids (RNA, DNA) and proteins (enzymes). The authors have now measured by 1H-NMR shift expts. the stability of binary stacks formed between purine nucleosides or nucleotides (N) and the indicator ligand 1,10-phenanthroline (Phen), and the authors also reviewed the related literature. Surprisingly, the stability of the (Phen)(N) adducts is largely independent of the type of purine residue involved, including deprotonation, e.g., at (N1)H of a guanine moiety, and also of the location of the phosphate group at the ribosyl ring. This contrasts with the self-stacking tendency which decreases within the series adenosine < guanosine < inosine < cytidine approx. uridine. The formation of an ionic (+/-) or metal ion (M2+) bridge stabilizes the formation of stacks as obsd., e.g., in mixed ligand Cu2+ complexes formed between Phen and AMP (5'-AMP2-); yet, in these instances the position of the phosphate group at the ribosyl ring affects the stability of the stacks: It decreases in the order 2'-AMP2- < 5'-AMP2- < 3'-AMP2- in the Cu(Phen)(AMP) complexes demonstrating a significant steric discrimination. The stability of stacks also depends on the size of the arom.-ring systems involved; as one would expect, purines stack better than pyrimidines and Phen generally better than 2,2'-bipyridine. Results obtained with various mixed ligand metal ion complexes contg. ATP (ATP4-) and an amino acid anion (Aa-) lead to the conclusion: The recognition of the adenine residue by the amino acid side chain in M(ATP)(Aa)3- complexes decreases in the series tryptophan (indole residue) < histidine (imidazole residue) < leucine (iso-Pr residue) < alanine (Me group). This type selectivity is certainly of relevance for amino acid/protein interactions with nucleotides/nucleic acids. The addn. of an org. solvent like 1,4-dioxane reduces the solvent polarity and decreases the stability of binary stacks like (Phen)(ATP)4- dramatically; in contrast, intramol. stacks, as present in Cu(Phen)(ATP)2-, are much less affected. Because the effective dielec. const. or permittivity in the active site cavity of an enzyme or a ribozyme is lower than in bulk water, Nature has here a further tool to achieve selectivity. Here it needs to be noted that the involved changes in free energy (ΔG0) are small; e.g., a formation degree of 20% of an intramol. stack in a mixed ligand complex corresponds only to -0.6 kJ mol-1 allowing Nature to shift such equil. easily.