Respiratory complex I is a key protein complex in cell bioenergetics. It efficiently converts chemical potential between NADH and ubiquinone into electrochemical potential across the bacterial or mitochondrial membrane. Despite many years of research and many reported high-resolution structures, the mechanism of coupling between the electrochemical reaction and generation of electrochemical trans-membrane potential remains a mystery. Still…
Like desperate polar explorers trying to reach the South Pole the first, many have been proposing the coupling mechanism of the protein, but the South Pole keep escaping us.
My laboratory has been working on trying to understand how complex I works, and Piotr Kolata, a PhD student, solved the structure of the simplest characterized complex I from bacteria Escherichia coli.
The structure revealed many interesting details of this simple complex I homolog. The most pronounced feature of the complex, however, was the instability of the connections between its peripheral arm which catalyzes the redox reaction, and the membrane arm which mediates the proton translocation across the membrane. Seeing how fragile this connection is, it is difficult to believe that the rearrangement of the polypeptide loops at the interface between the subunits mediates the coupling of this high-energy process. An equivalent of around 30 kT units of chemical energy is converted in each reaction cycle of complex I. That is a lot.
This made us think of whether a mechanism without interfacial loops moving can be thought about. Going through the different options we realized that a somewhat counter-intuitive hypothetical mechanism solved many problems.
In this putative mechanism, everything is very simple. Membrane module transport protons by alternating access mechanism, like many transporters do, whereas the peripheral arm mediates redox reaction like many enzymes do. No mysteries, no moving loops. One invention evolution did have to come up with to make this work. And that is creating a chamber at the interface of the arms that seals the cavity accessible to quinone from the solvent charges.
Who would have thought that the schematics of the mechanism would lead to a very much unexpected association ?..
And what about the complex I mechanism? I don’t think we know it yet, but one day we will. It is just a molecular machine. Molecular machines are simple. Simpler than it looks now.