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.