10.1021/jm0505112.s001
Dingguo Xu
Dingguo
Xu
Yanzi Zhou
Yanzi
Zhou
Daiqian Xie
Daiqian
Xie
Hua Guo
Hua
Guo
Antibiotic Binding to Monozinc CphA β-Lactamase from <i>Aeromonas </i><i>h</i><i>ydropila</i>:
Quantum Mechanical/Molecular Mechanical and Density Functional Theory
Studies
American Chemical Society
2005
Antibiotic Binding
ligand
Mechanical
substrate
zinc ion
Density Functional Theory Studies
antibiotic molecule
quantum region
charge density
DFT
CphA
lactam
500 ps
dynamics simulations
residue
apo enzyme
Aeromonas hydropila
hydrogen bond
QM
2005-10-20 00:00:00
Journal contribution
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
The active-site dynamics of apo CphA β-lactamase from <i>Aeromonas </i><i>hydropila</i> 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.