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 is the terminal respiratory enzyme of all
eukaryotes and many bacteria and archaea, reducing O to water and
harnessing the free energy from the reaction to generate the transmembrane
electrochemical potential. The diffusion of O 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, a homologous enzyme of cytochrome
aa in Thermus thermophilus, demonstrated that O
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, this
putative pathway appears partially occluded between the entrances and the
reduction site. Also, the experimentally determined second-order rate
constant for O delivery in cytochrome aa
(10Ms) is 10 times slower than that in
cytochrome ba (10Ms). A question
to be addressed is whether cytochrome aa utilizes this X-ray
inferred tunnel as the primary pathway for O delivery. Using
complimentary computational methods including multiple independent
flooding MD simulations and implicit ligand sampling calculations, we probe
the O delivery pathways in cytochrome aa of
Rhodobacter sphaeroides. All of the O 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 delivery pathway in cytochrome aa. The rate
constant for O delivery in cytochrome aa, approximated
using the simulation results, is 10 times slower than in cytochrome
ba, in agreement with the experimentally determined rate
constants.
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