The transphosphorylation step in the enzyme-catalyzed hydrolysis of phosphate eaters by Ribonuclease A (RNase A) is explored using ab initio quantum chemical methods. For the first time, components found in the RNase A active site are included in the all-electron chemical model, made up of 2-hydroxyethyl methyl phosphate monoanion used as the substrate, and small model compounds used to mimic the three important residues, His-12, His-119, and Lys-41, found in the RNase A active site. The remainder of the immediate active site, including ten residues and six bound water molecules, is treated using effective fragment potentials (EFPs) incorporated directly into the Hamiltonian of the quantum system. The EFPs, derived from separate quantum calculations on individual components, are constructed to accurately represent the correct electrostatics and polarization fields of each component. High-resolution X-ray crystallographic data are used to assign the fixed relative positions of each component in the quantum and EFP regions. Characterization of the salient stationary points along the transphosphorylation reaction pathway at the RHF level using a 3-21+G(d) basis set reveals several low-barrier proton transfer steps between the substrate and the active site residues which allow transphosphorylation to occur with modest activation, consistent with the experimental data. Moller-Plesset perturbation theory (MP2) and density functional theory methods utilizing a larger 6-31+G(d) basis are also used to explore the effects of electron correlation on the surface energetics. Consistent with expectations, the electrostatic field effects from the EFPs used to represent the non-participating parts of the active site are found to differentially stabilize certain structures along the reaction pathway.