A QM/MM investigation, based on a DFT(B3LYP)//Amber-ff99 potential, has been carried out to elucidate the mechanism of diaminopimelate epimerase. This enzyme catalyzes the reversible stereoconversion of one of the two stereocenters of diaminopimelate and represents a promising target for rational drug design aimed to develop new selective antibacterial therapeutic agents. The QM/MM computations show that the reaction proceeds through a highly asynchronous mechanism where the side-chain of a negatively charged Cys-73 (thiolate) deprotonates the R-carbon substrate. Simultaneously, the Cys-217 thiolic proton moves toward the same carbon atom on the opposite face, thus determining the configuration inversion. A fingerprint analysis provides a detailed description of the influence of the various residues surrounding the active site and clearly shows the electrostatic nature of the most important contributions to the catalysis.
ASJC Scopus subject areas
- Physical and Theoretical Chemistry
- Computer Science Applications