Molecular strain in the active/deactive-transition modulates domain coupling in respiratory complex I

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Biophysics

Background:

• Complex I is a crucial redox-driven proton pump in aerobic respiration, essential for ATP synthesis.
• Understanding the active (A) and deactive (D) states of Complex I is key to regulating its enzymatic turnover.
• The precise mechanism linking conformational states to Complex I activity remains largely unknown.

Purpose of the Study:

• To investigate how global motion during the A/D transition in Complex I influences its function.
• To elucidate the molecular mechanisms underlying the coupling between conformational states and enzyme activity.
• To provide a structural basis for understanding the modulation of biological activity by protein dynamics.

Main Methods:

• Utilized cryo-electron microscopy (cryo-EM) data of mammalian Complex I in active and deactive states.
• Analyzed molecular strain accumulation at specific coupling regions during the A/D transition.
• Investigated force propagation pathways between substrate binding and proton pumping machinery.

Main Results:

• Global motion along the A/D transition generates molecular strain at critical coupling sites.
• The A/D motion modulates force propagation, affecting redox chemistry and proton pumping.
• Evidence suggests altered electrostatic and conformational coupling across large distances due to A/D motion.

Conclusions:

• The A/D conformational transition in Complex I is intrinsically linked to its catalytic activity.
• Protein dynamics play a significant role in modulating the function of large molecular machines.
• This research provides a molecular framework for understanding Complex I regulation and function.