Interactions between Asp, His, Ser residues within models of the active site of serine proteases

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Abstract
Empirical theoretical calculations were performed on a simplified model of the active site of 2 serine proteases: .alpha.-chymotrypsin and subtilisin Novo. The stability of the catalytic triad and the H-bond formation between the Asp-His and His-Ser pairs were examined for different protonation states. The Asp-His interactions prevail over 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 a determinant for the stability of the triad in .alpha.-chymotrypsin. In subtilisin Novo, on the contrary, the presence of the neighboring residues seems to contribute more largely to the stability. Strong H-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. The mechanism of the proton transfer can probably occur only from perturbations of the active site structure induced by the presence of the substrate.

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