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Iron Hydroperoxide Intermediate in Superoxide Reductase: Protonation or Dissociation First? MM Dynamics and QM/MM Metadynamics Study
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posted on 2017-05-16, 00:00 authored by Rolf David, Hélène Jamet, Vincent Nivière, Yohann Moreau, Anne MiletSuperoxide reductase
is a mononuclear iron enzyme involved in superoxide
radical detoxification in some bacteria. Its catalytic mechanism is
associated with the remarkable formation of a ferric hydroperoxide
Fe3+-OOH intermediate, which is specifically protonated
on its proximal oxygen to generate the reaction product H2O2. Here, we present a computational study of the protonation
mechanism of the Fe3+-OOH intermediate, at different levels
of theory. This was performed on the whole system (solvated protein)
using well-tempered metadynamics at the QM/MM (B3LYP/AmberFF99SB)
level. Enabled by the development of a new set of force field parameters
for the active site, a conformational MM study of the Fe3+-OOH species gave insights into its solvation pattern, in addition
to generating the two starting conformations for the ab initio metadynamics setup. Two different protonation mechanisms for the
Fe3+-OOH intermediate have been found depending on the
starting structure. Whereas a possible mechanism involves at first
the protonation of the hydroperoxide ligand and then dissociation
of H2O2, the most probable one starts with an
unexpected dissociation of the HOO– ligand from
the iron, followed by its protonation. This favored reactivity was
specifically linked to the influence of both the nearby conserved
lysine 48 residue and the microsolvatation on the charge distribution
of the oxygens of the HOO– ligand. These data highlight
the crucial role of the whole environment, solvent, and protein, to
describe accurately this second protonation step in superoxide reductase.
This is clearly not possible with smaller models unable to reproduce
correctly the mechanistically determinant charge distribution.
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protonation mechanismsprotonation stepMM Dynamicswell-tempered metadynamicshydroperoxide ligandsuperoxide reductaseiron Hydroperoxide Intermediateprotonation mechanismOOH speciesiron enzymesolvated proteinmechanistically determinant charge distributionforce field parametersdissociationcharge distributionFeDissociation Firstlysine 48 residueH 2 O 2solvation patternMM studyHOOB 3LYP levelSuperoxide Reductaseab initio metadynamics setupreaction product H 2 O 2QM
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