The known structure of carbonic anhydrase includes the structure of the active site, which consists of Zn2+, coordinated to three histidine (His) residues and a water molecule. The ligand involved in the catalysis is the water molecule. Using imidazole (Im) to model histidine, it is found that histidine is the strongest bonding residue to Zn2+ of all neutral amino acid residues. On the basis of high-level ab initio calculations, the sequential bond energies for one to three imidazoles attached to Zn2+ were evaluated. The bond energy Zn(Im)(3)(2+)- (H2O) was also determined by ab initio calculations and (gas phase) ion equilibria measurements. From a comparison of the free energy of stabilization of Zn2+ in the enzyme and that in aqueous solution, we conclude that very strongly bonding residues such as histidine are essential to make the Zn2+ ion in the enzyme stable, relative to the aqueous environment. The strongly bonding histidine also has another more important role. Due to the very large charge transfer and polarizability energy component with such a ligand and ligand-ligand repulsion, the bonding to the fourth, i.e., the (HO)-O-2 Ligand, is very much weakened. It is shown that weakening of the Zn(L)(3)(2+)-(H2O) bond energy is unfavorable, i.e., increases the energy required for the first step of the accepted mechanism, Zn(His)(3)OH22+ -Zn(His)(3)OH+ + H+, while the second step, Zn(His)(3)OH+ + CO2 H2O/-> Zn(His)(3)(H2O)(2+) + HCO3-, is favorably affected, i.e. requires less energy. The choice of the ligands L therefore must be such so as to lead to a compromise between the two opposing effects. By making a semiquantitative inclusion of the solvent effect of the protein and aqueous environment on the reaction free energies for the above two ionic reactions, it was possible to shaw that the "choice" of the three histidine ligands is " just right" to provide this compromise. These Ligands lead to reaction free energies that are close to zero for both reactions.