The energetics of the catalytic reaction of ribonuclease A have been explored with empirical valence bond (EVB) simulations to elucidate the origin of the enormous catalytic power of this enzyme and to examine different mechanistic alternatives. The two mechanisms analyzed were a general acid-general base mechanism with a dianionic transition state and a triester-like mechanism with a monoionic transition state. The first step of the analysis used experimental information to determine the activation energy of each assumed mechanism in a water cage. This has provided an experimentally based reference point for the catalytic effect of the enzyme. The next step of the analysis involved EVE simulations of the reaction in water and calibrated these simulations against the above-mentioned energetics of the reference reaction. The simulations were performed in the protein environment without changing any EVE parameters. The catalysis was measured as the difference in the overall activation free energy of the respective mechanism in water and in protein. In the mechanism with the dianionic transition state a catalytic effect of similar to 18 +/- 6 kcal/mol was established which is in good agreement with the experimentally derived estimate of similar to 21 kcal/mol. In the mechanism with the monoionic transition state, a value of similar to 12 +/- 6 kcal/mol was calculated which is 5 kcal/mol lower than its estimated value, making it slightly less likely to be the actual mechanism in the enzyme. The origin of the catalytic power is attributed to an electrostatic reduction of the activation barriers. This reduction is associated with the preorganized polar environment of the enzyme.