A molecular dynamics and computational study of ligand docking and electron transfer in ferritins

The mechanism of the reductive release of iron from the cavity of the iron storage protein, ferritin, has been difficult to confirm on the molecular level using experimental studies. In this paper, we use a variety of computational tools to study the binding of flavin redox agents to the protein surface, and the subsequent electron transfer (ET) through the protein coat. Flavin binding sites are identified that represent efficient routes to reduction of Fe(III) across the protein coat in human and bacterial ferritins. Using the pathways model and Dutton's packing density model, we show that ET across the protein coat to nucleation sites is feasible. Different protein configurations for human heavy and light chain ferritin were obtained along classical molecular dynamics trajectories and used for flavin binding and ET studies. We find that protein configuration affects both the binding and ET rate constants significantly. We show that the maximum possible ET rate constants to the nucleation site GLU-61 in human heavy chain ferritin for protein configurations along a MD simulation trajectory can differ by about 8 orders of magnitude compared to the crystal structure and in human light-chain ferritin rate constants vary by about 4 orders of magnitude.