Iron is an important trace metal that is essential for the functioning of various biological systems and processes. Iron dysregulation has been linked to various disorders including neurodegeneration and cancer. A unique, iron-dependent type of regulated cell death called ferroptosis is believed to involve iron-catalyzed lipid peroxidation that occurs in the mitochondrio n or endoplasmic reticulum. To probe labile iron in the mitochondrion, we have studied a Szeto-Schiller (SS) peptide conjugated to an iron chelator, 8-hydroxyquinoline (8HQ), and a fluorophore (dansyl). In this work, we will describe atomistic molecular dynamics (MD) simulation studies of the interactions between the model SS peptide and a mitochondrial-mimicking membrane. Non-equilibrium MD simulations were also used to elucidate the mechanism of peptide translocation across the membrane at different velocities. The findings from these simulation studies reveal the mechanism of peptide entry and transport across the mitomembrane as well as associated energetic barriers.
