Second Coordination Sphere Effects on the Mechanistic Pathways for Dioxygen Activation by a Ferritin: Involvement of a Tyr Radical and the Identification of a Cation Binding Site

Ferritins are ubiquitous diiron enzymes involved in iron(II) detoxification and oxidative stress responses and can act as metabolic iron stores. The overall reaction mechanisms of ferritin enzymes are still unclear, particularly concerning the role of the conserved, near catalytic center Tyr residue. Thus, we carried out a computational study of a ferritin using a large cluster model of well over 300 atoms including its first‐ and second‐coordination sphere. The calculations reveal important insight into the structure and reactivity of ferritins. Specifically, the active site Tyr residue delivers a proton and electron in the catalytic cycle prior to iron(II) oxidation. In addition, the calculations highlight a likely cation binding site at Asp(65), which through long‐range electrostatic interactions, influences the electronic configuration and charge distributions of the metal center. The results are consistent with experimental observations but reveal novel detail of early mechanistic steps that lead to an unusual mixed‐valent iron(III)‐iron(II) center.