GROMOS-MD SIMULATIONS ON THE COENZYME THIAMIN DIPHOSPHATE IN APOENZYME ENVIRONMENT

Thiamin diphosphate (ThDP) is an essential cofactor for a number of en zymes, especially of pyruvate decarboxylase (PDC) which catalyzes the decarboxylation of a-keto acids. Recently, the crystal structure of PD C-bound ThDP has been determined. Based on these X-ray data molecular dynamics (MD) simulations of the isolated coenzyme as well as of ThDP in its enzymatic environment were performed, using the GROMOS87 softwa re package. In the ThDP-apoenzyme model all significant amino acid res idues with a cut-off radius less than 8.5 Angstrom from the cofactor w ere considered. The conformational behavior and the formation of speci fic structures of both ThDP and enzyme-bound ThDP were investigated in order to get hints on the activity and the mechanism of the coenzyme. Therefore, trajectories of significant structural parameters were ana lyzed by our graphics tool. Moreover, Ramachandran-like plots with res pect to significant torsion angles were used for the illustration. Fin ally, MD simulations on ThDP analogs with less or none catalytic activ ity and apoenzyme mutants were included, in order to study the cofacto r-apoenzyme binding. (C) 1998 John Wiley & Sons, Inc.