Molecular Aspects of Chemotherapy

Molecular dynamics simulations have been performed on two penicillin-recognizing proteins. One protein is an enzyme from Streptomyces R61 and has transpeptidase and carboxypeptidase activity on peptide substrates terminating in D-alanyl-D-alanine. The DD-peptidase is a model for penicillin-binding proteins (PBPs) controlling bacterial peptidoglycan biosynthesis and is inhibited by various classes of natural and synthetic f3-lactam antibiotics. The second protein is a f3-lactamase from Bacillus licheniformis 749/C and deactivates penicillins and other f3-lactam antibiotics by hydrolyzing them to inactive products. Crystallographic data for the two proteins have been refined by molecular mechanics energy mini-' mizations, and the conformation space available to the proteins immersed in an 8-A layer of water molecules has been explored by molecular dynamics simulations. The solid state model of the DD-peptidase is found to be much further from an energy-optimized structure than in the case of the f3-lactamase. The DD-peptidase is discovered to have a flexible loop that can transiently close access to the active site serine. An overview of recent modeling studies of 13and y-Iactam antibiotics illustrate the type of information that can be obtained with modem methodologies of computational chemistry.