We report here a transition path sampling study of the conformational fluctuation of His-64 that is known to be important in the enzymatic catalysis of human carbonic anhydrase II. The dynamical transition between experimentally detected conformations of His-64 could not be observed using classical molecular dynamics trajectories extended to 3.5 us, indicating the transition to be rare on the time scale of molecular dynamics. Using the transition path sampling method, ail ensemble of transition paths between these two conformers has been generated and analyzed in detail to identify the mechanism of coupling of His-64 to its neighboring residues during the conformational transition. It is found that both Asn-62 and Tyr-7 may contribute toward retaining the His-64 residue in its outward conformation. Trp-5, on the other hand, shows marked motions at the transition state. The number of water molecules inside a part of the active site cavity and the corresponding cavity volume are also found to vary coupled to the His-64 conformational dynamics.