Structural and energetic insights into Mn-to-Fe substitution in the oxygen-evolving complex

Manganese (Mn) serves as the catalytic center for water splitting in photosystem II (PSII), despite the abundance of iron (Fe) on earth. As a first step toward why Mn and not Fe is employed by Nature in the water oxidation catalyst, we investigated the Fe₄CaO₅ cluster in the PSII protein environment using a quantum mechanical/molecular mechanical (QM/MM) approach, assuming an equivalence between Mn(III/IV) and Fe(II/III). Substituting Mn with Fe resulted in the protonation of μ-oxo bridges at sites O2 and O3 by Arg357 and D1-His337, respectively. While the Mn₄CaO₅ cluster exhibits distinct open- and closed-cubane S₂ conformations, the Fe₄CaO₅ cluster lacks this variability due to an equal spin distribution over sites Fe1 and Fe4. The absence of a low-barrier H-bond between a ligand water molecule (W1) and D1-Asp61 in the Fe₄CaO₅ cluster may underlie its incapability for ligand water deprotonation, highlighting the relevance of Mn in natural water splitting.