TCB Publications - Abstract

Paween Mahinthichaichan, Robert B. Gennis, and Emad Tajkhorshid. Cytochrome aa3 oxygen reductase utilizes the tunnel observed in the crystal structures to deliver O2 for catalysis. Biochemistry, 57:2150-2161, 2018. (PMC: PMC5936630)

MAHI2018-ET 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, 12651278]. 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$_3$ ($\sim$10$^8$M$^{-1}$s$^{-1}$) is 10 times slower than that in cytochrome ba$_3$ ($\sim$10$^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 complimentary 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.

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