Hybrid QM/MM studies of serine protease catalysis and inhibition.

One of the most exptl. studied classes of enzymes is that of the serine protease family. Much attention has been focussed on finding inhibitors for these enzymes due to the potentially wide range of therapeutic possibilities. Traditional inhibitor design has focussed on complementary binding of substrates and does not exploit the specific nature of the catalytic triad of serine, histidine and aspartate amino acid residues, and the oxyanion hole which are conserved throughout the enzyme series. In this paper we present example studies of the reactivity of a range of protease enzymes using both ab initio and semi-empirical QM/MM methods. We discuss the similarities and anomalies of the reactions of trypsin, elastase and tryptase using selected models, natural substrates and inhibitors. The potential energy surfaces and mechanisms are compared with those of other enzyme systems. [on SciFinder (R)]