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Cytochrome aa 3 is the terminal respiratory enzyme of all eukaryotes and many bacteria and archaea, reducing O 2 to water and harnessing the free energy from the reaction to generate the transmembrane electrochemical potential. The diffusion of O 2 to the heme-copper catalytic site, which is buried deep inside the enzyme, is the initiation step of the reaction chemistry. Our previous molecular dynamics (MD) study with cytochrome ba 3 , a homologous enzyme of cytochrome aa 3 in Thermus thermophilus, demonstrated that O 2 diffuses from the lipid bilayer to its reduction site through a 25 Å long tunnel inferred by Xe binding sites detected by X-ray crystallography [Mahinthichaichan, P., Gennis, R., and Tajkhorshid, E. (2016) Biochemistry 55, 1265-1278]. Although a similar tunnel is observed in cytochrome aa 3 , this putative pathway appears partially occluded between the entrances and the reduction site. Also, the experimentally determined second-order rate constant for O 2 delivery in cytochrome aa 3 (∼10 8 M -1 s -1 ) is 10 times slower than that in cytochrome ba 3 (∼10 9 M -1 s -1 ). A question to be addressed is whether cytochrome aa 3 utilizes this X-ray-inferred tunnel as the primary pathway for O 2 delivery. Using complementary computational methods, including multiple independent flooding MD simulations and implicit ligand sampling calculations, we probe the O 2 delivery pathways in cytochrome aa 3 of Rhodobacter sphaeroides. All of the O 2 molecules that arrived in the reduction site during the simulations were found to diffuse through the X-ray-observed tunnel, despite its apparent constriction, supporting its role as the main O 2 delivery pathway in cytochrome aa 3 . The rate constant for O 2 delivery in cytochrome aa 3 , approximated using the simulation results, is 10 times slower than in cytochrome ba 3 , in agreement with the experimentally determined rate constants.

Cytochrome aa3 Oxygen Reductase Utilizes the Tunnel Observed in the Crystal Structures To Deliver O2 for Catalysis

Cytochrome aa₃ Oxygen Reductase Utilizes the Tunnel Observed in the Crystal Structures To Deliver O₂ for Catalysis