The RNA 2'OH activation as taking place in the first chemical step of self-cleaving ribozymes is studied theoretically by DFT and MP2 methods using a continuum solvation model (CPCM). The reaction of proton transfer is studied in the presence of two kinds of catalysts: a fully hydrated metal ion (Mg(2+)) or partially hydrated nucleobase (guanine), taken separately or together leading to three different modes of activation. The metal ion is either directly bound (inner-sphere) or indirectly bound (outer-sphere) to the 2'OH group and a hydroxide ion acts as a general or specific base; the nucleobase is taken in anionic or in neutral enol-tautomeric forms playing itself the role of general base. The presence of a close metal ion (outer-sphere) lowers the pK(a) value of the 2'OH group by several log units in both metal-ion and nuleobase catalysis. The direct metal coordination to the 2'OH group (inner-sphere) further stabilizes the developing negative charge on the nucleophile. The switching from the inner-sphere to the outer-sphere coordination appears to be driven by the energy cost for reorganizing the first coordination shell rather than by the electrostatic repulsion between the ligands. The metal-ion catalysis is more effective with a specific base in the dianionic mechanism. On the other hand, the nucleobase catalysis is more effective in the monoanionic mechanism and in the presence of a metal ion acting as a cofactor through nonspecific electrostatic interactions. The results establish a baseline to study the possible roles of metal and nucleobase catalysts and their environment in more realistic models for self-cleaving ribozymes.

Department of Laboratory Methods and Information Systems Faculty of Health and Social Studies University of South Bohemia J Boreckého 27 370 11 České Budějovice Czech Republic

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RNA Structural Dynamics As Captured by Molecular Simulations: A Comprehensive Overview

QM/MM studies of hairpin ribozyme self-cleavage suggest the feasibility of multiple competing reaction mechanisms