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Insights into the Acylation Mechanism of Class A β-Lactamases from Molecular Dynamics Simulations of the TEM-1 Enzyme Complexed with Benzylpenicillin

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Contribution from the Departamento de Química Física y Analítica, Universidad de Oviedo, C/ Julián Clavería 8, 33006 Oviedo, Spain, and Department of Chemistry, The Pennsylvania State University, 152 Davey Laboratory, University Park, Pennsylvania 16802-6300 USA
Cite this: J. Am. Chem. Soc. 2003, 125, 3, 672–684
Publication Date (Web):December 24, 2002
https://doi.org/10.1021/ja027704o
Copyright © 2003 American Chemical Society
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    Abstract

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    Herein, we present results from molecular dynamics MD simulations (∼1 ns) of the TEM-1 β-lactamase in aqueous solution. Both the free form of the enzyme and its complex with benzylpenicillin were studied. During the simulation of the free enzyme, the conformation of the Ω loop and the interresidue contacts defining the complex H-bond network in the active site were quite stable. Most interestingly, the water molecule connecting Glu166 and Ser70 does not exchange with bulk solvent, emphasizing its structural and catalytic relevance. In the presence of the substrate, Ser130, Ser235, and Arg244 directly interact with the β-lactam carboxylate via H-bonds, whereas the Lys234 ammonium group has only an electrostatic influence. These interactions together with other specific contacts result in a very short distance (∼3 Å) between the attacking hydroxyl group of Ser70 and the β-lactam ring carbonyl group, which is a favorable orientation for nucleophilic attack. Our simulations also gave insight into the possible pathways for proton abstraction from the Ser70 hydroxyl group. We propose that either the Glu166 carboxylate-Wat1 or the substrate carboxylate-Ser130 moieties could abstract a proton from the nucleophilic Ser70.

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    †

     Departamento de Química Física y Analítica, Universidad de Oviedo.

    §

     Current address:  Laboratoire de Dynamique Moleculaire, Institut Jean-Pierre Ebel, 41 rue Jules Horowitz, 38027 Grenoble, France.

    *

     To whom correspondence should be addressed. Fax:  +34-985103125.

    ‡

     Department of Chemistry, The Pennsylvania State University.

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    Benzylpenicillin parameters. Table showing the first peak position of g(r) and its integrated value (6 pages, print/PDF). This material is available free of charge via the Internet at http://pubs.acs.org.

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