Computational Modeling Study on Formation of Acyclic Clavulanate Intermediates in Inhibition of Class A β-Lactamase: Water-Assisted Proton Transfer

Molecular dynamics (MD) simulation and quantum chemical (QC) calculations were used to investigate the reaction mechanism of the formation of acyclic clavulanate intermediates in the inhibition of class A β-lactamase. The initial model for QC calculations was derived from an MD simulation. It was composed of a substrate clavulanate and four residues (Ser70, Gln237, Ser130, and Ser216), which form hydrogen bonds with the substrate. The QC calculation results indicate that the oxazolidine ring can undergo cleavage by proton transfer, which yields not only imine but also enamine products. A new mechanism involving hydrogen transfer from C6 to O1 has been suggested. Besides, MD simulation provided evidence that the water molecule can catalyze the proton transfer, and QC calculation shows water assistance can decrease the energy barrier greatly.