Hybrid QM/MM Calculations on the First Redox Step of the Catalytic Cycle of Bovine Glutathione Peroxidase GPX1

Juraj Kóňa; Walter M F Fabian

doi:10.1021/ct200129q

Hybrid QM/MM Calculations on the First Redox Step of the Catalytic Cycle of Bovine Glutathione Peroxidase GPX1

J Chem Theory Comput. 2011 Aug 9;7(8):2610-6. doi: 10.1021/ct200129q. Epub 2011 Jun 29.

Authors

Juraj Kóňa¹, Walter M F Fabian²

Affiliations

¹ Institute of Chemistry, Center for Glycomics, Slovak Academy of Sciences , Dúbravska cesta 9, 845 38 Bratislava, Slovak Republic.
² Institute of Chemistry, Karl Franzens University , Graz, Heinrichstrasse 28, A-8010 Graz, Austria.

PMID: 26606634
DOI: 10.1021/ct200129q

Abstract

The first reaction step of the redox cycle of bovine erythrocyte glutathione peroxidase from class 1 (GPX1) was investigated using hybrid quantum mechanics/molecular mechanics (QM/MM) calculations using the ONIOM methodology. The reduction of hydrogen peroxide by the active-site selenocysteine in selenolate form assisted by the Arg177 residue was modeled based on a proposal from previous molecular dynamics simulations and pKa calculations (J. Chem. TheoryComput. 2010, 6, 1670-1681). The redox reaction is predicted as a concerted SN2 nucleophilic substitution with a concomitant proton transfer from Arg177 onto leaving hydroxide ion upon reduction of hydrogen peroxide. The height of the reaction barrier was predicted in range of 6-11 kcal mol(-1), consistent with an experimental rate constant of ca. 10(7) M(-1) s(-1). The proposed GPX1-Se(-)-Arg177H(+) mechanism for GPX1 is compared with the GPX3-SeH-Gln83 one proposed for human glutathione peroxidase from class 3 (GPX3) and with the solvent-assisted proton exchange mechanism proposed for GPX-like organic selenols. The structural and energetic parameters predicted by various density functional theory methods (B3LYP, MPW1PW91, MPW1K, BB1K, M05-2X, M06-2X, and M06) are also discussed.