MOLECULAR-ORBITAL THEORETICAL-STUDY ON ACID-BASE PROPERTY AND REACTIVITY OF CHARGE RELAY SYSTEM IN ALPHA-CHYMOTRYPSIN

The acid-base property and reactivity of the charge relay system in .alpha.-chymotrypsin are studied by a molecular orbital theoretical method. It is shown that the observed pKa, about 7 in the activity of the enzyme, is a result of a compensation of a pKa raising effect of the basic assistance of Asp-102 to His-57 and a pKa lowering effect of the distorted H bond of the ligand water to His-57. The former effect raises the pKa of His-57 by about 4 pK units, but the latter lowers it by about the same amount, leading to apparent pKa about 7. Calculation on the H+ transfer energies in the charge relay system indicates that the H+ configuration with the anionic Asp-102 and the neutral His-57 is of the lowest energy, but the configuration with the neutral Asp-102 and the anionic His-57 lies at the energy not so far from the lowest energy configuration. The efficiency of the H+ abstraction from Ser-195 by the coupled system of His-57 and Asp-102 is high in spite of the distorted H bond between Ser-195 and His-57. Implications of these results for .alpha.-chymotrypsin catalysis are discussed.