title: Antibiotic binding to monozinc CphA beta-lactamase from Aeromonas hydropila: quantum mechanical/molecular mechanical and density functional theory studies.
abstract: The active-site dynamics of apo CphA beta-lactamase from Aeromonas hydropila and its complex with a beta-lactam antibiotic molecule (biapenem) are simulated using a quantum mechanical/molecular mechanical (QM/MM) method and density functional theory (DFT). The quantum region in the QM/MM simulations, which includes the Zn(II) ion and its ligands, the antibiotic molecule, the catalytic water, and an active-site histidine residue, was treated using the self-consistent charge density functional tight binding (SCC-DFTB) model. Biapenem is docked at the active site unambiguously, based on a recent X-ray structure of an enzyme-intermediate complex. The substrate is found to form the fourth ligand of the zinc ion with its 3-carboxylate oxygen and to hydrogen bond with several active-site residues. The stability of the metal-ligand bonds and the hydrogen-bond network is confirmed by 500 ps molecular dynamics simulations of both the apo enzyme and the substrate-enzyme complex. The structure and dynamics of the substrate-enzyme complex provide valuable insights into the mode of catalysis in such enzymes that is central to the bacterial resistance to beta-lactam antibiotics.
authors.affiliation: Department of Chemistry, University of New Mexico, Albuquerque, NM 87131, USA.
authors.forename: Dingguo
authors.initials: D
authors.lastname: Xu
authors.forename: Yanzi
authors.initials: Y
authors.lastname: Zhou
authors.forename: Daiqian
authors.initials: D
authors.lastname: Xie
authors.forename: Hua
authors.initials: H
authors.lastname: Guo
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry*; D001426:Bacterial Proteins / Q000737:chemistry*; D001665:Binding Sites; D002384:Catalysis; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011789:Quantum Theory; D013845:Thienamycins / Q000737:chemistry*; D014867:Water / Q000737:chemistry; D015032:Zinc / Q000737:chemistry*; D001618:beta-Lactamases / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D008024:Ligands; D013845:Thienamycins; D014867:Water; D001618:beta-Lactamases; C082063:cphA protein, Aeromonas hydrophila; D015032:Zinc; C065257:biapenem