© 2017 American Chemical Society. A proton shuttle mechanism for the phosphoryl transfer reaction in RNA, in which a proton is transferred from the nucleophile to the leaving group through a nonbridged oxygen atom of the phosphate, was explored using the MO6-2X density functional method and the solvent continuum model. This reaction is the initial step of the RNA hydrolysis. We used different solvents characterized by their dielectric constant, and, for each of them, we studied the nuclear and electronic relaxation, produced by the solvent reaction field, for the stationary points. Given that RNA has a poor leaving group, the bond breaking corresponds to the rate-determining step. If the O atom is substituted by a S atom, the leaving group is now good, and the rate-determining step is now the nucleophilic attack concerted with the proton transfer. The most relevant result we found is that none of the solvents we studied has a free energy of activation that is smaller than the one in water. This suggests that the enzyme catalysis following this mechanism must be due to the permanent electric field that is created by a preorganized charge distribution but not to the solvent reaction field.