Binding and catalysis of metallo-beta-lactamase studied using a SCC-DFTB/CHARMM
approach

Dingguo Xu1, Yanzi Zhou2, Daiqian Xie, dqxie@nju.edu.cn2, and Hua Guo,
hguo@unm.edu1. (1) Department of Chemistry, University of New Mexico,
Albuquerque, NM 87131, (2) Department of Chemistry, Nanjing University, China

The binding dynamics and first step of the beta-lactam hydrolysis reaction
catalyzed by a class B2 beta-lactamase are investigated using a quantum
mechanical/molecular mechanical (QM/MM) approach. The QM region, which includes
the catalytic zinc ion and its protein ligands, the antibiotic molecule, a
histidine side chain, and an active-site water, is treated with the
self-consistent charge density function tight binding (SCC-DFTB) method; while
the MM region is described by the CHARMM force field. The binding pattern is
found to agree with existing crystallographic data. The nucleophilic attack of
the substrate carbonyl carbon by the active-site water is found to be concerted
with the proton transfer to a metal-binding Asp residue. The resulting anionic
intermediate is stabilized by the metal ion, avoiding the formation of a
tetrahedral intermediate. The corresponding potential of mean force shows a
single barrier of 14 kcal/mol, in agreement with kinetic data.