We study the entry pathway of dioxygen into human ferritin by means of both first principles and classical molecular dynamics techniques. Oxygen molecules, which behave hydrophobically in the water solvent, are found to interact with the Tyr 29 residue of human ferritin both directly via weak interactions and indirectly via hydrophobic forces. These interactions drive O-2 toward a narrow hydrophobic channel which connects the ferroxidase site of ferritin with the external environment. Diffusion of O-2 through the channel is observed using locally enhanced sampling techniques, and the enthalpy barrier to diffusion is calculated from first principles. (C) 2004 Elsevier B.V. All rights reserved.