SUBSTRATE-SPECIFICITY OF CHYMOTRYPSIN - STUDY OF INDUCED STRAIN BY MOLECULAR MECHANICS

Acylenzyme intermediates, produced by transfer of the acyl portions of selected natural substrates onto the catalytic serine hydroxyl of the serine protease chymotrypsin, were modeled with the AMBER force field . The obtained structures were used to calculate interaction and defor mation energies. A set of 32 geometry variables were extracted out of each structure. They describe deformation effects specific for each su bstrate. It is shown by statistical analyses, that the interaction and deformation energies correspond to measured substrate reactivities. T he extracted geometry variables are able to reproduce this dependency through multivariante statistical methods. These analyses suggest that there exist specific deformations of both the substrate and the enzym e portion, which are related to substrate reactivity. The geometry cha nges observed for high specific substrates are interpreted in terms of mechanistical requirements of the enzymatic reaction. The obtained mo del validates the hypothesis of induced strain as possible source of s ubstrate specifity of chymotrypsin.