Molecular Orbital Studies on Serine, Cysteine, and Modified Proteases

Molecular orbital studies were carried out on α-chymotrypsin, papain, and thiolsubtilisin by using the complete neglect of differential overlap/2 method. By comparison between α-chymotrypsin and papain, the following results were obtained : (1) The proton transfer barrier from Cys-25 (neutral) to His-57 (neutral) is lower than that from Ser-195 (neutral) to His-57 (anion) in the"charge relay system"of α-chymotrypsin. (2) The active site of papain does not have the"charge relay system"and asparagine facilitates the proton transfer from cysteine to histidine. The results for thiolsubtilisin were as follows : (1) The hydrogen bond system structure in the active site is aspartate (neutral)-histidine (neutral)-cysteine (anion), and the"charge relay system"is broken by cysteine in place of serine. (2) Even though the effect of solvent is present, cysteine anion is stable. A"charge relay system"composed of aspartate, histidine, and water dimer was proposed from the calculations by using water dimer in place of serine.