Insights into functions of the H channel of cytochrome c oxidase from atomistic molecular dynamics simulations

Area of Science:

• Biochemistry
• Molecular Biology
• Biophysics

Background:

• A-type cytochrome c oxidase (CcO) is crucial for cellular respiration, terminating electron transport chains in mitochondria and bacteria.
• Three proton transfer pathways (D, K, and H channels) are proposed for CcO proton pumping.
• Previous studies suggest the H channel, rather than the D channel, might be the primary proton route in bovine mitochondrial CcO.

Purpose of the Study:

• To investigate the functional role of the H channel in proton transfer within bovine mitochondrial CcO.
• To elucidate the mechanism of proton translocation through the H channel using atomistic molecular dynamics simulations.

Main Methods:

• Atomistic molecular dynamics simulations of the entire and core structures of bovine CcO.
• Analysis of residue conformational fluctuations, hydration, and hydrogen bonding within the H channel.
• Assessment of proton transfer feasibility via His413 and the role of heme a's electric dipole moment.

Main Results:

• The H channel's upper and middle regions show adequate hydration and residues for potential proton conduction.
• Asp51 exhibits conformational fluctuations consistent with crystallographic data.
• No transient water networks supporting proton transfer via neutral His413 were observed.
• Sufficient hydration around His413 occurred only when protonated, but its pKa is too low for a direct transfer pathway.
• Simulations indicate the H channel may function as a dielectric well due to redox-state-dependent dipole moment changes.

Conclusions:

• The H channel in bovine CcO does not appear to be a direct proton transfer pathway via His413.
• The H channel likely plays a role as a dielectric well, influenced by the electric dipole moment changes around heme a.
• Further research is needed to fully understand the intricate proton transfer mechanisms in CcO.