| Carbonic anhydrase (CA), which catalyzes the interconversion of carbon dioxide to bicarbonate and an excess proton, is ubiquitous in nature. Due to its pivotal role in carbon dioxide transport and pH regulation the family of CA enzymes have become one of the most extensively characterized enzymes that utilize a proton transfer (PT) event. In human carbonic anhydrase II (HCA II), the fastest of at least 14 CA isozymes, the rate-limiting step involves the formation of an intramolecular water wire and the transfer of a proton across the active site cavity from the zinc-bound solvent to a proton shuttling residue (His64). The PT event in HCA II represents the boundary between proton transfer and proton transport via Grotthuss shuttling. This dissertation will utilize computer simulations to evaluate the HCA II enzyme's environmental effect on the orientation of the proton shuttling residue (His64), formation of the intramolecular water wire, and stabilization/destabilization of the excess proton in the rate limiting PT event. |
