Investigating the Many Roles of Internal Water in Cytochrome c Oxidase

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biology

Background:

• Cytochrome c oxidase (CcO) is vital for cellular respiration, catalyzing oxygen reduction and proton pumping.
• Proton transport in CcO is thought to involve internal water chains.
• Understanding CcO hydration is key to elucidating its catalytic mechanism.

Purpose of the Study:

• To analyze the hydration of CcO, including the Fe-Cu binuclear center (BNC), using the Dowser++ program.
• To compare computational hydration predictions with experimental X-ray data.
• To investigate the dynamic nature and dielectric properties of CcO's internal water.

Main Methods:

• Utilized the semi-empirical hydration program Dowser++.
• Analyzed high-resolution X-ray crystallographic data of CcO.
• Performed molecular dynamics simulations.
• Applied the Fröhlich-Kirkwood model to investigate dielectric constants.

Main Results:

• Dowser++ accurately predicted water molecules in CcO's D- and K-channels and near the BNC.
• The program predicted more internal waters than observed experimentally.
• No significant hydration was found in the catalytic cavity, supporting transient wetting models.
• Molecular dynamics explained discrepancies between predicted and observed water molecules.
• Calculated dielectric constants approached bulk water values in densely hydrated cavities.

Conclusions:

• Dowser++ is a valuable tool for studying CcO hydration.
• The study provides insights into the role of water in CcO's proton pumping mechanism.
• Results suggest that catalytic cavity hydration is likely transient or dependent on protein structural changes.