TY - DATA T1 - Iron Hydroperoxide Intermediate in Superoxide Reductase: Protonation or Dissociation First? MM Dynamics and QM/MM Metadynamics Study PY - 2017/05/16 AU - Rolf David AU - Hélène Jamet AU - Vincent Nivière AU - Yohann Moreau AU - Anne Milet UR - https://acs.figshare.com/articles/dataset/Iron_Hydroperoxide_Intermediate_in_Superoxide_Reductase_Protonation_or_Dissociation_First_MM_Dynamics_and_QM_MM_Metadynamics_Study/5049025 DO - 10.1021/acs.jctc.7b00126.s002 L4 - https://ndownloader.figshare.com/files/8545630 KW - protonation mechanisms KW - protonation step KW - MM Dynamics KW - well-tempered metadynamics KW - hydroperoxide ligand KW - superoxide reductase KW - iron Hydroperoxide Intermediate KW - protonation mechanism KW - OOH species KW - iron enzyme KW - solvated protein KW - mechanistically determinant charge distribution KW - force field parameters KW - dissociation KW - charge distribution KW - Fe KW - Dissociation First KW - lysine 48 residue KW - H 2 O 2 KW - solvation pattern KW - MM study KW - HOO KW - B 3LYP level KW - Superoxide Reductase KW - ab initio metadynamics setup KW - reaction product H 2 O 2 KW - QM N2 - Superoxide 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. ER -