title: Theoretical studies of the hydrolysis of antibiotics catalyzed by a metallo-β-lactamase.
abstract: In this paper, hybrid QM/MM molecular dynamics (MD) simulations have been performed to explore the mechanisms of hydrolysis of two antibiotics, Imipenen (IMI), an antibiotic belonging to the subgroup of carbapenems, and the Cefotaxime (CEF), a third-generation cephalosporin antibiotic, in the active site of a mono-nuclear β-lactamase, CphA from Aeromonas hydrophila. Significant different transition state structures are obtained for the hydrolysis of both antibiotics: while the TS of the CEF is an ionic species with negative charge on nitrogen, the IMI TS presents a tetrahedral-like character with negative charge on oxygen atom of the carbonyl group of the lactam ring. Thus, dramatic conformational changes can take place in the cavity of CphA to accommodate different substrates, which would be the origin of its substrate promiscuity. Since CphA shows only activity against carbapenem antibiotic, this study sheds some light into the origin of the selectivity of the different MbL and, as a consequence, into the discovery of specific and potent MβL inhibitors against a broad spectrum of bacterial pathogens. We have finally probed that a re-parametrization of semiempirical methods should be done to properly describe the behavior the metal cation in active site, Zn(2+), when used in QM/MM calculations.
authors.affiliation: Departament de Química Física i Analítica, Universitat Jaume I, 12071 Castellón, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Meliá
authors.affiliation: Departament de Química Física i Analítica, Universitat Jaume I, 12071 Castellón, Spain. Electronic address: sferrer@uji.es.
authors.forename: S
authors.initials: S
authors.lastname: Ferrer
authors.affiliation: Departament de Química Física i Analítica, Universitat Jaume I, 12071 Castellón, Spain. Electronic address: moliner@uji.es.
authors.forename: V
authors.initials: V
authors.lastname: Moliner
authors.affiliation: Departament de Química, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Bertran
mesh_terms: D016980:Aeromonas hydrophila / Q000201:enzymology; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D020134:Catalytic Domain; D006868:Hydrolysis; D015378:Imipenem / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D001618:beta-Lactamases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D015378:Imipenem; D001618:beta-Lactamases
keywords: CEF; CphA; Enzyme promiscuity; IMI; Mono zinc MβLs; QM/MM