Ligand‐pK_a Shifts through Metals: Potential Relevance to Ribozyme Chemistry

Abstract

Functional and crystallographic analyses of catalytically active RNA molecules ('ribozymes') have revealed a multitude of different routes by which nature accomplishes cleavage reactions of the RNA sugar-phosphate backbone. While there is agreement that these reactions involve general acid-base chemistry, the choice of 'acid' and of 'base' appears to be quite versatile. Among the numerous surprises that have emerged from these studies in recent years is the phenomenon of 'shifted pK(a) values' of nucleobases, hence, the fact that pK(a) values of isolated nucleobases in H(2)O can be shifted in either direction--upward or downward--into the physiological pH range, and that consequently allows these nucleobases to function as 'acids' or 'bases'. Another change in paradigm in recent years relates to the role of divalent metal ions in these catalytic reactions, which points to the possibility of an indirect involvement in the catalytic cycle rather than necessarily to a direct participation, as in the case with the hepatitis delta virus ribozyme. In this review, basic features of nucleobases and/or aqua ligand pK(a) shifts caused by metal coordination and H-bonding are discussed.

Bifacial Base‐Pairing Behaviors of 5‐Hydroxyuracil DNA Bases through Hydrogen Bonding and Metal Coordination

“…This result showedt hat the U OH -A base pairing was site-selectively disrupted by the binding of Gd III ions to the U OH bases. [17] Ta ken all together, the hybridization preferenceo ft he U OHcontaining strand 3 can be alteredb ym etal coordination. In the absence of metal ions, the strand 3 prefers to hybridize with its "complementary"s trands 4A through the hydrogenbonded U OH -A base pairing.…”

“Directed” Assembly of Metallacalix[n]arenes with Pyrimidine Nucleobase Ligands of Low Symmetry: Interchanging Metals in Mixed‐Metal Metallacalix[4]arenes and Incorporating Additional Metals at the Exocyclic Groups

“…[9] Strongly shifted pK a values are a common feature of a metal-bearing rare nucleobase tautomer, as observed by us in numerous other cases. [16] The fact that, unlike with 2 and 3, two separate protonation steps for 1 are observed (DpK a % 1.3) most likely is a consequence of the formation of homo-cytosine pairs of 1 a (Scheme 2), which represent metalated analogues of the natural cytosine pairs present in the i-motif. [17] The major difference between these two types of pairs is that the formation of 1 a is shifted towards pH % 8.…”

Rare Tautomers of 1‐Methyluracil and 1‐Methylthymine: Tuning Relative Stabilities through Coordination to PtII Complexes

“…[35] There are at least two factors facilitating Pt II binding to N3 at pH values well below the pK a of N(3)H (Scheme 7): First, initial Pt II binding to O4 and/or O2 of the canonical tautomer will acidify the proton at N3. [36] Second, the aquated cisplatin carries its own base Pt À OH (pK a1 of cis-…”