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Binding of benzylpenicillin to metallo-beta-lactamase: A QM/MM study

Olsen, L; Rasmussen, Torben LU ; Hemmingsen, L and Ryde, Ulf LU (2004) In The Journal of Physical Chemistry Part B 108(45). p.17639-17648
Abstract
Metallo-beta-lactamases are bacterial enzymes that may function with either one or two zinc ions bound in the active site. In this work, the binding of benzylpenicillin to mono-zinc metallo-beta-lactamase from Bacillus cereus has been investigated in a docking procedure applying a combined quantum mechanical/molecular mechanical method as the final step. It is demonstrated that the substrate can bind with the carbonyl oxygen of the lactam ring coordinating to the zinc ion, and with the zinc-bound hydroxide ion in position for a nucleophilic attack on the carbonyl carbon of the lactam ring. In some structures, both the histidine and the cysteine at the other (unoccupied) metal-binding site are in a proper position to function as proton... (More)
Metallo-beta-lactamases are bacterial enzymes that may function with either one or two zinc ions bound in the active site. In this work, the binding of benzylpenicillin to mono-zinc metallo-beta-lactamase from Bacillus cereus has been investigated in a docking procedure applying a combined quantum mechanical/molecular mechanical method as the final step. It is demonstrated that the substrate can bind with the carbonyl oxygen of the lactam ring coordinating to the zinc ion, and with the zinc-bound hydroxide ion in position for a nucleophilic attack on the carbonyl carbon of the lactam ring. In some structures, both the histidine and the cysteine at the other (unoccupied) metal-binding site are in a proper position to function as proton shuttles in proton transfer from the previously zinc-bound hydroxide, to the nitrogen in the lactam ring. In addition, the hydrophobic region formed by Phe34, Val39, Trp59, and Ala89 interacts with the phenyl group of benzylpenicillin, whereas the carboxylate group may be stabilized by Lys171 and Asn180. Alternatively, the carboxylate can bind to the zinc ion, prohibiting the nucleophilic attack of the zinc-bound hydroxide on the lactam carbonyl carbon. However, such a structure is energetically disfavored compared to the other enzyme-substrate complexes. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
The Journal of Physical Chemistry Part B
volume
108
issue
45
pages
17639 - 17648
publisher
The American Chemical Society
external identifiers
  • wos:000224993900052
  • scopus:9144235573
ISSN
1520-5207
DOI
10.1021/jp0482215
language
English
LU publication?
yes
id
6350093e-6d18-47a6-9683-4c05d5b504f8 (old id 139558)
date added to LUP
2007-07-17 12:18:34
date last changed
2017-01-01 07:06:06
@article{6350093e-6d18-47a6-9683-4c05d5b504f8,
  abstract     = {Metallo-beta-lactamases are bacterial enzymes that may function with either one or two zinc ions bound in the active site. In this work, the binding of benzylpenicillin to mono-zinc metallo-beta-lactamase from Bacillus cereus has been investigated in a docking procedure applying a combined quantum mechanical/molecular mechanical method as the final step. It is demonstrated that the substrate can bind with the carbonyl oxygen of the lactam ring coordinating to the zinc ion, and with the zinc-bound hydroxide ion in position for a nucleophilic attack on the carbonyl carbon of the lactam ring. In some structures, both the histidine and the cysteine at the other (unoccupied) metal-binding site are in a proper position to function as proton shuttles in proton transfer from the previously zinc-bound hydroxide, to the nitrogen in the lactam ring. In addition, the hydrophobic region formed by Phe34, Val39, Trp59, and Ala89 interacts with the phenyl group of benzylpenicillin, whereas the carboxylate group may be stabilized by Lys171 and Asn180. Alternatively, the carboxylate can bind to the zinc ion, prohibiting the nucleophilic attack of the zinc-bound hydroxide on the lactam carbonyl carbon. However, such a structure is energetically disfavored compared to the other enzyme-substrate complexes.},
  author       = {Olsen, L and Rasmussen, Torben and Hemmingsen, L and Ryde, Ulf},
  issn         = {1520-5207},
  language     = {eng},
  number       = {45},
  pages        = {17639--17648},
  publisher    = {The American Chemical Society},
  series       = {The Journal of Physical Chemistry Part B},
  title        = {Binding of benzylpenicillin to metallo-beta-lactamase: A QM/MM study},
  url          = {http://dx.doi.org/10.1021/jp0482215},
  volume       = {108},
  year         = {2004},
}