Charge Transfer and Chemo-Mechanical Coupling in Respiratory Complex I.

Area of Science:

• Biochemistry and Molecular Biology
• Bioenergetics
• Structural Biology

Background:

• The mitochondrial respiratory chain synthesizes ATP using energy from catabolic processes.
• Complex I, a key component, couples electron transfer from NADH to quinone reduction and proton pumping.
• Understanding the interplay between redox-driven conformational changes and proton pathways in Complex I is crucial but incomplete.

Purpose of the Study:

• To investigate the chemo-mechanical coupling between iron-sulfur cluster redox changes and conformational transitions in Thermus thermophilus Complex I.
• To elucidate the molecular mechanisms underlying quinone binding, release, and proton translocation.
• To identify key residues and molecular pathways involved in Complex I function.

Main Methods:

• Utilized microsecond-scale molecular dynamics simulations based on the crystal structure of Thermus thermophilus Complex I.
• Performed free-energy calculations to assess quinone binding affinities.
• Analyzed hydrogen-bond networks and residue functional classes.

Main Results:

• Identified allosteric redox switches coupling quinone binding pocket dynamics to NADH reduction.
• Demonstrated higher menaquinone affinity than menaquinol, facilitating menaquinol release and favoring menaquinone for charge transport.
• Revealed long-range hydrogen-bond networks essential for proton pumping from the quinone-binding site to transmembrane subunits.

Conclusions:

• The study reveals molecular design principles linking redox reactions, quinone turnover, and proton translocation in Complex I.
• Computational findings are consistent with experimental data and suggest new mutation targets for functional studies.
• Highlights the specific role of menaquinone and its interactions in Thermus thermophilus Complex I function.