How does the protein environment optimize the thermodynamics of thiol sulfenylation? Insights from model systems to QM/MM calculations on human 2-Cys peroxiredoxin

Abstract

Protein thiol/sulfenic acid oxidation potentials provide a tool to select specific oxidation agents, but are experimentally difficult to obtain. Here, insights into the thiol sulfenylation thermodynamics are obtained from model calculations on small systems and from a quantum mechanics/molecular mechanics (QM/MM) analysis on human 2-Cys peroxiredoxin thioredoxin peroxidase B (Tpx-B). To study thiol sulfenylation in Tpx-B, our recently developed computational method to determine reduction potentials relatively compared to a reference system and based on reaction energies reduction potential from electronic energies is updated. Tpx-B forms a sulfenic acid (R-SO⁻) on one of its active site cysteines during reactive oxygen scavenging. The observed effect of the conserved active site residues is consistent with the observed hydrogen bond interactions in the QM/MM optimized Tpx-B structures and with free energy calculations on small model systems. The ligand effect could be linked to the complexation energies of ligand L with CH₃S⁻ and CH₃SO⁻. Compared to QM only calculations on Tpx-B’s active site, the QM/MM calculations give an improved understanding of sulfenylation thermodynamics by showing that other residues from the protein environment other than the active site residues can play an important role.

Keywords:

• redox chemistry
• sulfenylation
• peroxiredoxin
• ligand effect
• QM/MM

Acknowledgments

The authors thank Jeremy Harvey (University of Bristol) for useful discussions. JO acknowledges the financial support of a EU Marie Curie ERG Fellowship (Project ‘Oestrometab’), of a Bolyai János Research Fellowship and of the New Széchenyi Plan (TÁMOP-4.2.2/B-10/1-2010-0009). GR thanks the FWO for a post doctoral fellowship. GR, FDP, and LvB wish to acknowledge financial support of the Research Foundation Flanders (FWO) through research program FWOAL622.

Notes

1. ChemShell, a Computational Chemistry Shell, see www.chemshell.org.