Unraveling the Nature of the Catalytic Power of Fluoroacetate Dehalogenase

Sebastián Miranda-Rojas, Israel Fernández, Johannes Kästner, Alejandro Toro-Labbé, Fernando Mendizábal

Index: 10.1002/cctc.201701517

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Abstract

Abstract Fluoroacetate dehalogenase is able to cleavage a carbon–fluoride bond, the strongest carbon–halogen bond in nature, in a process initiated by a SN2 reaction. The role of the enzyme machinery and particularly of the halogen pocket in the SN2 reaction is thoroughly explored by using state-of-the-art computational tools. A comparison between the non-catalyzed versus enzyme-catalyzed reaction, as well as with a mutant of the enzyme (Tyr219Phe), is presented. The energy barrier changes are rationalized by means of reaction force analysis and the activation strain model coupled with energy decomposition analysis. The catalysis is in part caused by the reduction of structural work from bringing the reactant species towards the proper reaction orientation, and the reduction of the electrostatic repulsion between the nucleophile and the substrate, which are both negatively charged. In addition, catalysis is also driven by an important reduction of the electronic reorganization processes during the reaction, where Tyr from the halogen pocket acts as a charge acceptor from the SN2 reaction axis therefore reducing the electronic steric repulsion between the reacting parts. Fluoroacetate dehalogenase: The inner working of fluoroacetate dehalogenase enzymatic machinery was revealed for the catalysis of the SN2 elementary step through the rationalization of electronic and structural contributions to the reaction barrier.