Ribozymes utilize diverse catalytic strategies. We report systematic quantum chemical calculations mapping the catalytic space of RNA cleavage by comparing all chemically feasible reaction mechanisms of RNA self-cleavage, using appropriate model systems including those chemical groups that may directly participate in ribozyme catalysis. We calculated the kinetics of uncatalyzed cleavage reactions proceeding via both monoanionic and dianionic pathways, and explicitly probed effects of various groups acting as general bases (GBs) and/or general acids (GAs), or electrostatic transition state stabilizers. In total, we explored 115 different mechanisms. The dianionic scenarios are generally preferred to monoanionic scenarios, although they may compete with one-another under some conditions. Direct GA catalysis seems to exert the dominant catalytic effect, while GB catalysis and electrostatic stabilization are less efficient. Our results indirectly suggest that the dominant part of the catalytic effect might be explained by the shift of the reaction mechanism from the mechanism of uncatalyzed cleavage to the mechanism occurring in ribozymes. This would contrast typical protein enzymes, primarily achieving catalysis by overall electrostatic effects in their catalytic center.

Institute of Biophysics of the Czech Academy of Sciences Kralovopolská 135 612 65 Brno Czech Republic

Regional Centre of Advanced Technologies and Materials Department of Physical Chemistry Faculty of Science Palacký University tř 17 listopadu 12 771 46 Olomouc Czech Republic

Scuola Internazionale Superiore di Studi Avanzati via Bonomea 265 34136 Trieste Italy

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