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

Abstract

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 beta-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.

Reaction pathway and free energy barrier for urea elimination in aqueous solution

“…So, the dominant reaction pathway for urea elimination in aqueous solution should be the water-assisted. It is not surprising because it has been known that water-assisted proton transfer generally helps to lower the energy barrier [5,40–44]. The calculated free energy barrier of 25.3 kcal/mol for the dominant reaction pathway of urea elimination in aqueous solution is in good agreement with available experimental kinetic data [14].…”