Cavity hydration dynamics in cytochrome c oxidase and functional implications

Area of Science:

• Biochemistry
• Biophysics
• Computational Biology

Background:

• Cytochrome c oxidase (CcO) generates proton gradients essential for cellular energy production.
• Understanding the molecular mechanisms of CcO's proton transfer efficiency is crucial but incomplete.
• Internal cavity hydration dynamics are proposed as a key regulatory factor.

Purpose of the Study:

• To investigate the energetics and timescales of volume and hydration changes in CcO's central cavity.
• To elucidate the molecular determinants regulating cavity hydration and its role in proton transport.
• To model the contribution of cavity hydration to the vectorial efficiency of CcO.

Main Methods:

• Atomistic molecular dynamics simulations (accumulatively >4 μs).
• Free energy computations for various CcO chemical states.
• Markov-state model analysis of extensive simulation trajectories (2 μs).

Main Results:

• Cavity volume and hydration are regulated by heme a3 propionate protonation, heme a redox state, and Glu286 protonation.
• Hydration level changes occur on the 100-200 ns timescale, preceding proton-loading site protonation.
• Cavity wetting transitions exhibit energetic and kinetic features supporting their regulatory role.

Conclusions:

• Reversible hydration-level changes in the central cavity are a key factor in regulating proton transfer pathways.
• This hydration dynamics mechanism contributes significantly to the vectorial efficiency of proton transport by CcO.
• The findings provide a molecular-level understanding of CcO's proton transfer regulation.