The active site of carbonic anhydrase II is investigated by a widely used model system ([Zn(NH3)(3)(HCO3)-(H2O)(n)(CH3OH)(m)](+), n = 0, 1, 2 and m = 0, 1) to explore the proton transfer within zinc-bound bicarbonate by quantum chemical methods. This proton transfer is a key step in the reversible hydration reaction of carbon dioxide, and although it is not the rate-limiting step in the overall reaction, its mechanism is heavily debated. Kinetic data of the system are computed by variational transition-state theory with tunneling corrections based on high-level quantum chemical methods such as coupled cluster and Gaussian-3 variants. From our data, it can be concluded that the proton transfer in Lipscomb fashion involves at least one proton-transfer mediating water molecule, and the Thr199 is shown to play a key role as proton donor/acceptor entity, especially in the backward reaction (the dehydration of bicarbonate). The availability of the hydroxy group of Thr199 has been approved by a 50 ps semiempirical QM/MM simulation. The uncatalyzed proton transfer in the hydration reaction reveals a reaction barrier of more than 30 kcal/mol. If catalyzed by one water molecule and the OH-group of threonine, this barrier decreases to less than 10 kcal/mol. The catalyzed model reaction is shown to yield reaction rates of more than 10(8) s(-1), thus being much faster than the rate-limiting step of the carbon dioxide conversion by carbonic anhydrase II. Our results therefore do not rule out the Lipscomb mechanism as a possible proton-transfer step, in contrast to various other studies, in which it is rejected with energetic arguments. Tunneling is shown to have significant effects in this part of the catalytic cycle even at room temperature by enhancing the reaction rate by more than I order of magnitude.