A conformational approach to the study of the dynamics of enzyme inhibition: studies on thermolysin

Abstract

The preferred conformations of β -phenylpropionyl-^L-phenylalanine (β -PPP) and N-carbobenzoxy-L-phenylalanine Cb_z-Phe), two inhibitors of thermolysin, have been determined by computing potential energy using empirial potential energy functions. Of the 15 to 20 conformations that are favoured for each of these inhibitors only a few have the right conformation to reach the active site of the enzyme. The conformer of β -PPP that initiates binding with the enzyme is different from the bound one, while for Cb_z-Phe the bound and initiating conformers are quite similar. Thus, β -PPP favours the 'induced fit' model while Cb_z-Phe follows the 'lock and key' model of binding. The inhibitors differ in their alignment at the active site.