All images were taken from the same top view of the enzyme. a) Highly occupied O2 regions characterized by the 3D density map calculated using the combined last 40-ns trajectories of five independent simulations. One region, which appears in a Y-shaped form, is the pathway that has been found to deliver O2 to the active site (green-dashed box). It is connected to the membrane via two branches, which we refer to and label as Branches A and B. Red-solid isosurfaces represent O2 partitioning free energy (ΔGi,sol) of −3.5 kcal/mol. b) The O2 delivery pathway. Purple-solid and red-wireframe isosurfaces correspond to ΔGi,sol of −4.0 and −3.0 kcal/mol, respectively. c) Xe binding sites identified by X-ray crystallography.35,40 Xe atoms were detected in a hydrophobic tunnel, displayed as a yellow-transparent surface using a probe radius of 1.8Å; they are numbered according to PDB entry 3BVD.35 The O2 delivery pathway identified in the present study (b) largely overlaps with this Xe-bound tunnel.