We report molecular dynamics simulations of the enzyme human carbonic anhydrase II (HCAII) inhibited by the azide anion (N-3(-)) using a quantum mechanical/molecular mechanical coupled potential. Experimentally, the azide ion binds to HCAII such that the structure of the active site is retained. This is interesting because the hydrogen bond interaction between the zinc-bound hydroxyl hydrogen and the hydroxyl oxygen of Thr-199 in the native enzyme is replaced by what formally appears to be a repulsive interaction between the hydroxyl oxygen of Thr-199 and the zinc-bound azide nitrogen. Two possibilities were considered for this system : First, the binding of hydrogen azide (N3H) was considered, but we conclude based on experimental (i.e., pK(a)s) and theoretical information that it is unlikely that this is what is bound to HCAII at physiological pH. When we bound the azide anion to the zinc ion in the HCAII active site we also found that the structure of the active site was retained. Upon further inspection, we determined that the reason for this has to do with the preferred azide resonance structure which placed extra positive charge on the central azide nitrogen, which allowed for favorable electrostatic interactions between the zinc-bound azide and the hydroxyl oxygen of Thr-199. This preferred enzyme resonance structure was 3.2 kcal/mol less stable than an alternative resonance structure in the gas phase when bound to zinc. Thus, HCAII is controlling the preferred resonance structure for the azide anion.