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.


Download Full Text

The manuscripts available on our site are provided for your personal use only and may not be retransmitted or redistributed without written permissions from the paper's publisher and author. You may not upload any of this site's material to any public server, on-line service, network, or bulletin board without prior written permission from the publisher and author. You may not make copies for any commercial purpose. Reproduction or storage of materials retrieved from this web site is subject to the U.S. Copyright Act of 1976, Title 17 U.S.C.

Download full text: Journal