DIFFERENT PROTONATION STATES OF THE BACILLUS CEREUS BINUCLEAR ZINC METALLO-β-LACTAMASE ACTIVE SITE STUDIED BY COMBINED QUANTUM MECHANICAL AND MOLECULAR MECHANICAL SIMULATIONS
Gu, Wei; Zhu, J.; Liu, H. Y.
2002 • In Journal of Theoretical and Computational Chemistry
DIFFERENT PROTONATION STATES OF THE BACILLUS CEREUS BINUCLEAR ZINC METALLO-β-LACTAMASE ACTIVE SITE STUDIED BY COMBINED QUANTUM MECHANICAL AND MOLECULAR MECHANICAL SIMULATIONS
Publication date :
2002
Journal title :
Journal of Theoretical and Computational Chemistry
ISSN :
0219-6336
Publisher :
World Scientific Publishing Company
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
Three different protonation states of the active site of the Bacillus cereus zinc-β-lactamase in its binuclear form are studied using combined quantum mechanics/molecular mechanics molecular dynamics simulations. The reliability of the quantum mechanical model, the self-consistent-charge density-functional-based tight binding method, in describing the zinc centers are tested through comparisons with ab initio quantum mechanical results. We found that this model gave relatively accurate results for structures and performed much better than the MNDO type semi-empirical method for the particular systems. The enzyme simulations suggested that when the overall charge of the active site is +1, i.e., both Asp90 and Wat1 (a water molecule coordinated with the first zinc ion) deprotonated, the second zinc ion is coordinated with Asp90 and Wat1, and a second water molecule cannot coordinate with the second zinc ion. When the overall charge is +2, i.e., either Asp90 or Wat1 protonated, Asp90 and Wat1 form a stable hydrogen bond. Depending on the proton being on Asp90 or on Wat1, the active site structure produced by the simulations is either similar to molecule A or to molecule B, both contained in the same crystal structure that has two enzyme molecules in a single asymmetric unit. The simulations of the +2 charge states also reproduced the experimentally observed "loose" coordination around the second zinc for the Bacillus Cereus enzyme. Based on the simulations and a gas phase potential energy surface scanning using ab initio model, we argue that the penta-coordination around the second zinc ion is not a stable arrangement. Mechanistic implications of these results are discussed.
Read More: http://www.worldscientific.com/doi/abs/10.1142/S0219633602000038
