Catalytic roles for proton transfer and protonation in ribozymes

Utilization of proton transfer in catalysis, which is well known in the mechanisms of protein enzymes, has been described only relatively recently for RNA enzymes. In this article, we present a current understanding of proton transfer by nucleic acids. Rate enhancement and specificity conferred by general acid-base catalysis are discussed. We also present possibilities for electrostatic catalysis from general acids and bases as well as cationic base pairs. The microenvironments of a large RNA provide the possibility of histidine-like pK(a)s for proton transfer, as well as lysine- and arginine-like pK(a)s for electrostatic catalysis. Discussion on proton transfer focuses on the hepatitis delta virus (HDV) and hairpin ribozymes, with select examples drawn from the protein literature. Discussion on electrostatic catalysis also draws on these two ribozymes, and a postulate for electrostatic catalysis by a cationic base pair in the mechanism of peptidyl transfer in the ribosome is presented. We also provide a perspective on possibilities for phosphoryl transfer mechanisms involving phosphorane intermediates and unusual tautomeric forms of the bases. Lastly, a distinction is made between ground state and "transition state" pK(a)s. We favor a model in which changes in pH lead to changes in the distribution of reactive and nonreactive ionizations of the ribozyme molecules in the ground state, and therefore suggest that "pK(a) changes in the transition state" do not provide an acceptable explanation for observed pH-rate profiles.