Proton-coupled electron transfer modulates the metal release of blood serum iron transferrin

Serum transferrin (sTf) is a key iron-transport protein in vertebrates, exhibiting an extraordinary affinity for Fe(III). Typically, only ∼30% of sTf is saturated with Fe(III), leaving a significant fraction of its binding sites available for other metal ions, including heavy metals and radionuclides. While iron release under endosomal pH is well-understood to proceed via protonation mechanisms, the release pathways at physiological pH remain less clear and are subject to multiple competing mechanisms. To address this, we employed extensive multi-scale modelling—combining molecular dynamics, metadynamics, and electronic structure calculations—to probe Fe(III) release under physiological conditions. Our investigations focused on three key pathways: direct protonation, one-electron reduction, and proton-coupled electron transfer (PCET). Calculated reduction potentials of approximately 1.3 V for both synthetic and protein models indicate that direct reduction is thermodynamically unfavourable, consistent with experimental observations.