Formation and spontaneous oxidation of neutral [4Fe–4S] clusters in prebiotic oceans

Iron‑sulfur clusters are enzyme cofactors essential to life and are proposed to form the basis of earliest metabolisms. Fe–S rhomb and cubane clusters require both Fe(II) and Fe(III) for stability, but the Archean ocean was dominated by reduced Fe(II). We hypothesize that protons could have served as an oxidant of Fe(II) to Fe(III) during cluster assembly. Concomitantly, coordinating ligands that complete the tetrahedral geometry of the iron sites in the molecular cubane clusters may have assured cluster stability and facilitated proton reduction. Density functional theory calculations suggest that protons delivered by H₃O⁺, Fe(SH)⁺, or H₂S can oxidize [2Fe–2S] clusters and promote the formation of cationic [4Fe–4S] clusters. The relative energetics of mackinawite-like (FeS)_n(aq) neutral nanoparticle sheets and ligated cationic [4Fe–4S] cubanes further indicate that ligands, such as water, bisulfide, and bioligands (such as short peptides) indeed play a key role in trapping cubane cluster states along the process of mackinawite-like nanoparticle sheet formation. Together, the redox reaction by protons and ligand coordination could have enabled molecular Fe–S cluster cofactor assembly directly from the Fe(II)-rich, sulfide-bearing waters of early Earth.