title: Molecular dynamics simulations of the mononuclear zinc-beta-lactamase from Bacillus cereus complexed with benzylpenicillin and a quantum chemical study of the reaction mechanism.
abstract: Herein, we present results from MD simulations of the Michaelis complex formed between the B. cereus zinc-beta-lactamase enzyme and benzylpenicillin. The structural and dynamical effects induced by substrate-binding, the specific role of the conserved residues, and the near attack conformers of the Michaelis complex are discussed. Quantum chemical methods (HF/6-31G* and B3LYP/6-31G*) are also applied to study the hydrolysis reaction of N-methylazetidinone catalyzed by a monozinc system consisting of the side chains of the histidine residues (His86, His88, and His149) complexed with Zn-OH and the side chains of Asp90 and His210. From this model system, we built molecular-mechanics representations of the prereactive complex and transition state configurations docked into the active site. Linear-scaling semiempirical calculations coupled with a continuum solvent model were then performed on these static models. We propose that the experimental rate data for the B. cereus enzyme is compatible with a one-step mechanism for the hydrolysis of beta-lactam substrates in which His210 acts as a proton donor.
authors.affiliation: Departamento de Química Física y Analítica, Universidad de Oviedo, Julián Clavería 8, 33006 Oviedo, Asturias, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Díaz
authors.forename: D
authors.initials: D
authors.lastname: Suárez
authors.forename: K M
authors.initials: KM
authors.lastname: Merz
mesh_terms: D001409:Bacillus cereus / Q000201:enzymology*; D003198:Computer Simulation; D006868:Hydrolysis; D008958:Models, Molecular; D010400:Penicillin G / Q000737:chemistry* / Q000378:metabolism; D010406:Penicillins / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D011789:Quantum Theory; D013816:Thermodynamics; D015032:Zinc / Q000737:chemistry* / Q000378:metabolism; D001618:beta-Lactamases / Q000737:chemistry* / Q000378:metabolism
chemical_list: D010406:Penicillins; D001618:beta-Lactamases; D015032:Zinc; D010400:Penicillin G