J. Am. Chem. Soc. 1997, 119, 6423-6431
6423
Acylation of β-Lactams by Class A β-Lactamase: An ab Initio Theoretical Study on the Effects of the Oxy-Anion Hole Brian D. Wladkowski,* Sarah A. Chenoweth, Julie N. Sanders, Morris Krauss, and Walter J. Stevens* Contribution from the Department of Chemistry, Western Maryland College, Two College Hill, Westminster, Maryland 21157, and Center for AdVanced Research in Biotechnology, National Institute of Standards and Technology, 9600 Gudelsky DriVe, RockVille, Maryland 20850 ReceiVed October 23, 1996X
Abstract: The initial acylation step in the β-lactamase catalyzed hydrolysis of β-lactams is studied using an ab initio quantum mechanical approach. The computational model incorporates a simple β-lactam substrate and key residues found in the active site in order to assess the plausibility of a specific mechanism originally proposed by Strynadka et al.1 and to estimate the stabilizing effects of the oxy-anion hole components founds in these enzymes. The computational model was constructed using information obtained from a high resolution X-ray crystal structure of unbound native β-lactamase, isolated from Staphylococcus aureus PC1. Within this model, the overall acylation reaction was found to occur with modest activation energy
