Dioxygen Activation by Caenorhabditis elegans Ferritin: The Effect of the Second‐Coordination Sphere on O ₂ Reduction to H ₂ O ₂

Ferritins are important proteins that store and detoxify iron. They contain a diiron active site that can convert dioxygen into hydrogen peroxide. The active site contains many hydrogen bonding interactions and charged residues, and hence, the precise mechanism is not well defined. In this work, a comprehensive computational study using molecular dynamics and quantum mechanics is presented on the structure and reactivity of dioxygen binding at the diiron(II) active site of a ferritin from the worm Caenorhabditis elegans . The molecular dynamics simulation gives a rigid protein structure due to the large number of polar interactions between residues and solvent water molecules. The calculated dioxygen activation is stepwise with two successive proton transfer steps via an iron(III)‐hydroperoxo intermediate. The calculations provide novel insight into the role of the strictly conserved near‐active site Tyr residue, which appears to be important for hydrogen bonding and positioning of dioxygen into the active site.