%0 Journal Article
%A Xu, Dingguo
%A Zhou, Yanzi
%A Xie, Daiqian
%A Guo, Hua
%D 2005
%T Antibiotic Binding to Monozinc CphA β-Lactamase from Aeromonas hydropila:
Quantum Mechanical/Molecular Mechanical and Density Functional Theory
Studies
%U https://acs.figshare.com/articles/journal_contribution/Antibiotic_Binding_to_Monozinc_CphA_Lactamase_from_i_Aeromonas_i_i_h_i_i_ydropila_i_Quantum_Mechanical_Molecular_Mechanical_and_Density_Functional_Theory_Studies/3261712
%R 10.1021/jm0505112.s001
%2 https://acs.figshare.com/ndownloader/files/5099407
%K Antibiotic Binding
%K ligand
%K Mechanical
%K substrate
%K zinc ion
%K Density Functional Theory Studies
%K antibiotic molecule
%K quantum region
%K charge density
%K DFT
%K CphA
%K lactam
%K 500 ps
%K dynamics simulations
%K residue
%K apo enzyme
%K Aeromonas hydropila
%K hydrogen bond
%K QM
%X The active-site dynamics of apo CphA β-lactamase from Aeromonas hydropila and its complex
with a β-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 β-lactam antibiotics.
%I ACS Publications