title: Understanding the acylation mechanisms of active-site serine penicillin-recognizing proteins: a molecular dynamics simulation study.
abstract: Beta-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 beta-lactams. Antibiotic resistance is mainly due to the production of beta-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 beta-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 pK(a) calculations have also been done to determine their protonation state. We analyze the differences between the beta-lactamase TEM-1, the membrane-bound PBP2x of Streptococcus pneumoniae, and the soluble DD-transpeptidase of Streptomyces K15.
authors.affiliation: Laboratoire de Dynamique Moléculaire, Institut de Biologie Structurale Jean-Pierre Ebel, CEA/CNRS Grenoble, France.
authors.forename: Mónica
authors.initials: M
authors.lastname: Oliva
authors.forename: Otto
authors.initials: O
authors.lastname: Dideberg
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Field
mesh_terms: D000215:Acylation; D001426:Bacterial Proteins; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D003198:Computer Simulation; D006602:Hexosyltransferases; D006860:Hydrogen Bonding; D046911:Macromolecular Substances; D008958:Models, Molecular; D002267:Muramoylpentapeptide Carboxypeptidase / Q000737:chemistry* / Q000378:metabolism; D046915:Penicillin-Binding Proteins; D010406:Penicillins / Q000737:chemistry* / Q000378:metabolism; D010458:Peptidyl Transferases; D012694:Serine / Q000737:chemistry*; D001618:beta-Lactamases / Q000737:chemistry* / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D002352:Carrier Proteins; D046911:Macromolecular Substances; D046915:Penicillin-Binding Proteins; D010406:Penicillins; C072223:PBP 2x protein, Streptococcus; D012694:Serine; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase; D001618:beta-Lactamases; C034413:beta-lactamase TEM-1