Combined QM/MM molecular dynamics simulations have been carried out to investigate the vibrational frequency shift for the azide antisymmetric stretch mode induced by aqueous solvation and by carbonic anhydrase II. In this work the oscillator and the enzyme active site is treated explicitly by quantum mechanics. Thus, the dynamical change of the potential energy surface of the oscillator can be adequately represented. We found that although the average geometry of the azide ion is symmetric in aqueous solution, the instantaneous solute−solvent interactions induce localization of the resonance structure having triple bond character, leading to a blue shift in the observed antisymmetric vibrational frequency in polar solvents. The computed frequency shift of azide ion from water to the active site of carbonic anhydrase is 56 cm-1, in good accord with the experimental value of 51 cm-1. Analyses of the computational results demonstrate that the origin of the protein-induced blue shift is due to a combination ...