The proton pumping mechanism of the bc1 complex. 2021

Roger Springett
Cardiovascular Division, King's College London British Heart Foundation Centre of Excellence, London, United Kingdom. Electronic address: roger.springett@kcl.ac.uk.

The bc1 complex is a proton pump of the mitochondrial electron transport chain which transfers electrons from ubiquinol to cytochrome c. It operates via the modified Q cycle in which the two electrons from oxidation of ubiquinol at the Qo center are bifurcated such that the first electron is passed to Cytc via an iron sulfur center and c1 whereas the second electron is passed across the membrane by bL and bH to reduce ubiquinone at the Qi center. Proton pumping occurs because oxidation of ubiquinol at the Qo center releases protons to the P-side and reduction of ubiquinone at the Qi center takes up protons from the N-side. However, the mechanisms which prevent the thermodynamically more favorable short circuit reactions and so ensure precise bifurcation and proton pumping are not known. Here we use statistical thermodynamics to show that reaction steps that originate from high energy states cannot support high flux even when they have large rate constants. We show how the chemistry of ubiquinol oxidation and the structure of the Qo site can result in free energy profiles that naturally suppress flux through the short circuit pathways while allowing high rates of bifurcation. These predictions are confirmed through in-silico simulations using a Markov state model.

UI MeSH Term Description Entries
D008956 Models, Chemical Theoretical representations that simulate the behavior or activity of chemical processes or phenomena; includes the use of mathematical equations, computers, and other electronic equipment. Chemical Models,Chemical Model,Model, Chemical
D009097 Multienzyme Complexes Systems of enzymes which function sequentially by catalyzing consecutive reactions linked by common metabolic intermediates. They may involve simply a transfer of water molecules or hydrogen atoms and may be associated with large supramolecular structures such as MITOCHONDRIA or RIBOSOMES. Complexes, Multienzyme
D011522 Protons Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. Hydrogen Ions,Hydrogen Ion,Ion, Hydrogen,Ions, Hydrogen,Proton
D003575 Cytochromes c1 The 30-kDa membrane-bound c-type cytochrome protein of mitochondria that functions as an electron donor to CYTOCHROME C GROUP in the mitochondrial and bacterial RESPIRATORY CHAIN. (From Enzyme Nomenclature, 1992, p545) Cytochrome c1,Cytochrome c-1,Cytochrome c 1
D004583 Electrons Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called CATHODE RAYS. Fast Electrons,Negatrons,Positrons,Electron,Electron, Fast,Electrons, Fast,Fast Electron,Negatron,Positron
D013816 Thermodynamics A rigorously mathematical analysis of energy relationships (heat, work, temperature, and equilibrium). It describes systems whose states are determined by thermal parameters, such as temperature, in addition to mechanical and electromagnetic parameters. (From Hawley's Condensed Chemical Dictionary, 12th ed) Thermodynamic
D017136 Ion Transport The movement of ions across energy-transducing cell membranes. Transport can be active, passive or facilitated. Ions may travel by themselves (uniport), or as a group of two or more ions in the same (symport) or opposite (antiport) directions. Antiport,Ion Cotransport,Ion Exchange, Intracellular,Symport,Uniport,Active Ion Transport,Facilitated Ion Transport,Passive Ion Transport,Cotransport, Ion,Exchange, Intracellular Ion,Intracellular Ion Exchange,Ion Transport, Active,Ion Transport, Facilitated,Ion Transport, Passive,Transport, Active Ion,Transport, Ion
D017494 Proton Pumps Integral membrane proteins that transport protons across a membrane. This transport can be linked to the hydrolysis of ADENOSINE TRIPHOSPHATE. What is referred to as proton pump inhibitors frequently is about POTASSIUM HYDROGEN ATPASE. H(+) Pump,H+ Pump,Proton Pump,Pump, H+,Pump, Proton,Pumps, Proton
D045303 Cytochromes b Cytochromes of the b group that have alpha-band absorption of 563-564 nm. They occur as subunits in MITOCHONDRIAL ELECTRON TRANSPORT COMPLEX III. Cytochrome b,Apocytochrome b

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