Iron has tremendous biological importance it reacts with oxygen (O2 ) and readily switches between the ferrous (Fe2+) and ferric (Fe3+ ) states. It plays a role in electron transfer reactions and in some enzymes that catalyze reactions of cellular oxidation as a result of its capacity to form a variety of coordination complexes with organic ligands. The concentration of iron in the body must be tightly regulated.
Ferritins are a family of proteins involved in iron storage found in bacteria, plants and animals with similar structures. They are symmetrical proteins with 120-140 Angstrom diameter (Fig. 1) and composed of 24 subunits. The subunits self-assemble to form a spherical molecule with an internal ~ 80 Å diameter cavity. At the ferritin catalytic sites Fe(II) is rapidly (milisecond) oxidized to the diferric peroxo intermediate and then to the diferric oxo product. After oxidation/reduction reaction with dioxygen or peroxide at the protein catalytic sites, it makes ferric oxy dimers which translocates to the ferritin cavity and is stored there as hydrated ferric iron oxide nanocrystal with a very low solubility. It is still poorly understood how Fe(II) reaches the catalytic ferroxidase sites deeply buried inside the ferritin subunits within the four-helix bundle. We study the process of uptake of iron ions (Fe2+ ) through the ion channels into the human ferritin and to the ferroxidase sites by means of all atom classical molecular dynamics (MD) simulations. The binding sites along the channel and the pathway of ions are investigated. From our simulation results we conclude that the 3-unit channels are the primary entrance passage way for iron ions which transport from the cytoplasm to the ferroxidase sites. There are several binding sites along the channel and en route to the catalytic sites. No iron ions exits (“retreats”) from the ferritin during the simulation time. Fe2+ ions have stronger binding to the binding sites inside the channel compared to Na+ ions, which have one positive charge and a larger diameter.
Metal Binding Sites of Human H-chain Ferritin and Iron Transport Mechanism to the Ferroxidase Sites: A Molecular Dynamics Simulation Study. Rozita Laghaei, Deborah G. Evans and Rob D. Coalson Proteins: Structure, Function, and Bioinformatics, 2013; 81, 1042–1050.
Poisson–Nernst–Planck (PNP) theory is a continuum electro-diffusion model in which the mobile ions are treated as a concentration profile. The motion and distribution of the ions are influenced by electrostatic forces. PNP theory requires self-consistent solution of the Poisson equation and drift-diffusion equations for all the ionic species moving through the channel. We are calculating the iron ion effective transit time from the exterior (bulk solution) to the interior of the ferritin with discrete and deep binding sites along the three-unit channels.
Calculation of Iron Transport through Human H-chain Ferritin.
Rozita Laghaei,William Kowallis, Deborah G. Evans and Rob D. Coalson
J. Phys. Chem. A. 2014; 118, 7442-7453.
