Theoretical investigation on the restoring step of the carbonic anhydrase catalytic cycle for natural and promiscuous substrates

Abstract

In the present study steered molecular dynamics simulations were applied to investigate the unbinding process of the complex of human carbonic anhydrase with the natural HCO3(-) and promiscuous H2NCOHN(-) products. This process is crucial for restoring the catalytic cycle of the enzyme. This investigation set out to give further insights on the release mechanism involved in the case of the promiscuous product believed suicide inhibitor for the hCAII against the natural final product. In particular, on the basis of the NPT molecular dynamics simulations performed on the bicarbonate, the penta-coordinated complex with the water is observed, while in the case of the ureate the same event does not take place. At this purpose the calculated potential of mean force based on the steered molecular dynamics (SMD) simulations shed light on an optimal pathway for the releasing of the products.

Keywords: Bicarbonate; Binding energy; Enzymatic catalytic turnover; SMD; Ureate; hCAII.