Hydration-Controlled Proton Transport in Respiratory Complex I

Area of Science:

• Biochemistry
• Molecular Biology
• Mitochondrial Respiration

Background:

• Proton pumping by respiratory complex I is crucial for mitochondrial ATP synthesis.
• The exact mechanism linking ubiquinone reduction to proton translocation remains unclear.
• A proposed lateral pathway involves ND1, ND3, and ND4L subunits, with potential hydration-dependent regulation.

Purpose of the Study:

• To elucidate the mechanism of proton translocation initiation in respiratory complex I.
• To investigate the role of hydration in proton transfer through the proposed lateral pathway.
• To understand the regulation of proton pumping at the molecular level.

Main Methods:

• Multiscale reactive molecular dynamics (MS-RMD) simulations.
• Analysis of water wire connectivity.
• Thermodynamic feasibility assessment of proton transfer coupled to hydration.

Main Results:

• Proton transfer is thermodynamically feasible under conditions of transient hydration and excess proton availability.
• Strong coupling between local hydration and proton transfer (PT) was identified in complex I.
• Proton injection dynamically enhances local hydration, opening the proton transfer pathway.

Conclusions:

• Hydration plays a critical role in regulating proton pumping in respiratory complex I.
• The findings support a model where dynamic hydration controls the onset of proton translocation.
• This mechanism is essential for efficient ATP synthesis in mitochondria.