Reduction potentials and acidity constants of Mn superoxide dismutase calculated by QM/MM free-energy methods

Jimmy Heimdal, Markus Kaukonen, Martin Srnec, Lubomír Rulíšek, Ulf Ryde*

*Corresponding author for this work

Research output: Contribution to journalArticleScientificpeer-review

31 Citations (Scopus)

Abstract

We used two theoretical methods to estimate reduction potentials and acidity constants in Mn superoxide dismutase (MnSOD), namely combined quantum mechanical and molecular mechanics (QM/MM) thermodynamic cycle perturbation (QTCP) and the QM/MM-PBSA approach. In the latter, QM/MM energies are combined with continuum solvation energies calculated by solving the Poisson-Boltzmann equation (PB) or by the generalised Born approach (GB) and non-polar solvation energies calculated from the solvent-exposed surface area. We show that using the QTCP method, we can obtain accurate and precise estimates of the proton-coupled reduction potential for MnSOD, 0.30±0.01 V, which compares favourably with experimental estimates of 0.26-0.40 V. However, the calculated potentials depend strongly on the DFT functional used: The B3LYP functional gives 0.6 V more positive potentials than the PBE functional. The QM/MM-PBSA approach leads to somewhat too high reduction potentials for the coupled reaction and the results depend on the solvation model used. For reactions involving a change in the net charge of the metal site, the corresponding results differ by up to 1.3 V or 24 pK a units, rendering the QM/MM-PBSA method useless to determine absolute potentials. However, it may still be useful to estimate relative shifts, although the QTCP method is expected to be more accurate.

Original languageEnglish
Pages (from-to)3337-3347
Number of pages11
JournalChemPhysChem
Volume12
Issue number17
DOIs
Publication statusPublished - 9 Dec 2011
MoE publication typeA1 Journal article-refereed

Keywords

  • acidity constants
  • enzymes
  • free-energy perturbation
  • molecular modelling
  • reduction potentials

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