Interactions between Asp, His, Ser residues within models of the active site of serine proteases. A theoretical empirical study.
Empirical theoretical calculations have been performed on a simplified model of the active site of two serine proteases: alpha-chymotrypsin and subtilisin Novo. The stability of the catalytic triad and the hydrogen bond formation between the Asp-His and His-Ser pairs have been examined for different protonation states. The results show that the Asp-His interactions prevail upon the His-Ser ones. Agreement between calculated configurations and the crystal structure of the site suggests that the presence of other residues near the functional residues is not determinant for the stability of the triad in alpha-chymotrypsin. In subtilisin Novo, on the contrary, the presence of the neighbouring residues seems to contribute more largely to the stability. Strong hydrogen bond interactions between the His and Ser residues do not exist in the resting enzymes. Any improvement of the His-Ser interactions requires large destabilization of the Asp-His diad. Our results suggest that the mechanism of the proton transfer can occur only from perturbations of the active site structure induced by the presence of the substrate.
D001224:Aspartic Acid; D001665:Binding Sites; D002918:Chymotrypsin; D004151:Dipeptides; D010450:Endopeptidases; D006639:Histidine; D008958:Models, Molecular; D011487:Protein Conformation; D012694:Serine; D012697:Serine Endopeptidases; D013329:Structure-Activity Relationship; D013381:Subtilisins
D004151:Dipeptides; D001224:Aspartic Acid; D012694:Serine; D006639:Histidine; D010450:Endopeptidases; D012697:Serine Endopeptidases; D013381:Subtilisins; D002918:Chymotrypsin