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Insight into the mechanism of the IMP‐1 metallo‐β‐lactamase by molecular dynamics simulations

Oelschlaeger, Peter and Schmid, Rolf D. and Pleiss, Jürgen (2003) Insight into the mechanism of the IMP‐1 metallo‐β‐lactamase by molecular dynamics simulations. Protein Engineering, 16 (5). pp. 341-350. ISSN 0269-2139. doi:10.1093/protein/gzg049.

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Two models, a purely nonbonded model and a cationic dummy atom approach, were examined for the modeling of the binuclear zinc‐containing IMP‐1 metallo‐β‐lactamase in complex with a mercaptocarboxylate inhibitor. The cationic dummy atom approach had substantial advantages as it maintained the initial, experimentally determined geometry of the metal‐containing active site during molecular dynamics simulations in water. The method was extended to the modeling of the free enzyme and the enzyme in complex with a cephalosporin substrate docked in an intermediate structure. For all three systems, the modeled complexes and the tetrahedral coordination of the zinc ions were stable. The average zinc–zinc distance increased by ~1 Å in the substrate complex compared with the inhibitor complex and the free enzyme in which a hydroxide ion acts as a bridging ligand. Thus, the zinc ions are predicted to undergo a back and forth movement upon the cycle of hydrolysis. In contrast to previous assumptions, no interaction of the Asn167 side chain with the bound cephalosporin substrate was observed. Our observations are in agreement with quantum‐mechanical calculations and experimental data and indicate that the cationic dummy atom approach is useful to model zinc‐containing metallo‐β‐lactamases as free proteins, in complex with inhibitors and in complex with substrates.

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Additional Information:© 2003 Oxford University Press. Received October 21, 2002; revised March 7, 2003; accepted March 23, 2003. This work was supported by the German Federal Ministry of Education and Research (project PTJ 31/0312702).
Funding AgencyGrant Number
German Federal Ministry of Education and ResearchPTJ 31/0312702
Subject Keywords:beta-lactam hydrolysis; metalloprotein; metallo-beta-lactamase; molecular dynamics simulation; zinc coordination
Issue or Number:5
Record Number:CaltechAUTHORS:20111020-085422332
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:27323
Deposited By: Tony Diaz
Deposited On:24 Oct 2011 22:23
Last Modified:09 Nov 2021 16:47

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