Understanding the acylation mechanisms of active-site serine penicillin-recognizing proteins: A molecular dynamics simulation study

Publisher Website
Google Scholar
Abstract
β‐Lactam antibiotics inhibit enzymes involved in the last step of peptidoglycan synthesis. These enzymes, also identified as penicillin‐binding proteins (PBPs), form a long‐lived acyl‐enzyme complex with β‐lactams. Antibiotic resistance is mainly due to the production of β‐lactamases, which are enzymes that hydrolyze the antibiotics and so prevent them reaching and inactivating their targets, and to mutations of the PBPs that decrease their affinity for the antibiotics. In this study, we present a theoretical study of several penicillin‐recognizing proteins complexed with various β‐lactam antibiotics. Hybrid quantum mechanical/molecular mechanical potentials in conjunction with molecular dynamics simulations have been performed to understand the role of several residues, and pKa calculations have also been done to determine their protonation state. We analyze the differences between the β‐lactamase TEM‐1, the membrane‐bound PBP2x of Streptococcus pneumoniae, and the soluble DD‐transpeptidase of Streptomyces K15. Proteins 2003.