QM Cluster or QM/MM in Computational Enzymology: The Test Case of LigW-Decarboxylase.

Mario Prejanò,Nino Russo,Tiziana Marino

doi:10.3389/fchem.2018.00249

Abstract

The catalytic mechanism of the decarboxylation of 5-carboxyvanillate by LigW producing vanillic acid has been studied by using QM cluster and hybrid QM/MM methodologies. In the QM cluster model, the environment of a small QM model is treated with a bulky potential while two QM/MM models studies include partial and full protein with and without explicitly treated water solvent. The studied reaction involves two sequential steps: the protonation of the carbon of the 5-carboxy-vanillate substrate and the decarboxylation of the intermediate from which results deprotonated vanillic acid as product. The structures and energetics obtained by using three structural models and two density functionals are quite consistent to each other. This indicates that the small QM cluster model of the presently considered enzymatic reaction is appropriate enough and the reaction is mainly influenced by the active site.

Highlights

Enzymes are biological machines that efficiently catalyze a huge number of chemical reactions in the very short time steps required by the physiological processes
Our own N-layered integrated molecular orbital and molecular mechanics (ONIOM) method was applied as the quantum mechanical (QM)/molecular mechanics level (MM) method in the framework of electronic embedding scheme, in which the effects of the fixed MM charges are incorporated in the QM hamiltonian (Svensson et al, 1996; Vreven et al, 2006)
We have considered the path for the bicarbonate release but our calculated PESs with the three models used give very high energetic barriers that are not compatible with the enzymatic kinetics

Summary

Introduction

Enzymes are biological machines that efficiently catalyze a huge number of chemical reactions in the very short time steps required by the physiological processes. Computational enzymology has become a very useful tool for studying enzyme activity since it allows to determine the energies and structures of short-lived intermediates and transition states. Different reaction pathways can be analyzed, and their feasibility can be established by a careful analysis of calculated energy barriers. A crucial issue in computational enzymology is the choice of the model to be used in the simulations. The choice is not so obvious because it depends on the nature of enzyme (without or with metal cofactor) on the catalytic pocket and on the amino acids implicated in the chemical reaction. In fully quantum mechanical (QM) treatment (Himo, 2006; Ramos and Fernandes, 2008; Siegbahn and Himo, 2011; Merz, 2014), a cluster that contains all the residues around the active site is considered

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Conclusion