An effective interaction model is presented linking high-level quantum chemistry to a structured environment via semiclassical interaction operators resembling effective core potentials. The model gives transferable results equivalent to a quantum chemical treatment of the complete system. This is applied to calculations of the reaction-pathway for carbonic anhydrase in which a zinc hydroxide species attacks CO2. The reaction path is shown to be compressed by the substrate-peptide contacts so that the end point structures have partial chemical bonds. The controversial binding structure for cyanate inhibitor was found to be closely related to the CO2 bound state due to a proton abstractionfacilitated by the enzyme. A mutation to link carbonic anhydrase with other hydrolysis metalloenzymes is also examined. The model accuracy for large systems is confirmed by reproductions of crystal structures as local energy minima and by the approximate agreement of the reaction energetics with known free energies.