The catalytic function of active site amino acid side chains in well-characterized enzymes

Although the kinetics and types of reactions carried out by enzymes have been established for some time, the detailed chemistry performed by these catalysis is largely unknown. Their geometries and compositions are very different from those found in conventional chemistry and understanding their mechanisms will open new areas of chemistry and make important contributions to the rational design of pharmaceuticals. We have formulated a computational method for determining the electronic role of amino acid residues in the active sites of enzymes that have been well characterized by high resolution spectroscopy and other physical chemistry techniques. Ab initio electronic structure calculations with a good basis set were employed, and solvent and dielectric effects were taken into account. Applications were made to ribonuclease A, the serine proteases, the labile hydrogen bonds in acid proteases (pepsin), and carbonic anhydrase.