title: Reduction potentials and acidity constants of Mn superoxide dismutase calculated by QM/MM free-energy methods.
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.
authors.affiliation: Department of Theoretical Chemistry, Lund University, Chemical Centre, P. O. Box 124, 221 00 Lund, Sweden.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Heimdal
authors.forename: Markus
authors.initials: M
authors.lastname: Kaukonen
authors.forename: Martin
authors.initials: M
authors.lastname: Srnec
authors.forename: Lubomír
authors.initials: L
authors.lastname: Rulíšek
authors.forename: Ulf
authors.initials: U
authors.lastname: Ryde
mesh_terms: D056004:Molecular Dynamics Simulation; D010084:Oxidation-Reduction; D011522:Protons; D011789:Quantum Theory; D012997:Solvents / Q000737:chemistry; D013482:Superoxide Dismutase / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D011522:Protons; D012997:Solvents; D013482:Superoxide Dismutase