The structure of the key bioenergetic enzyme respiratory complex I was resolved by cryo electron microscopy at a high resolution. Combined with state-of-the-art molecular simulations the new structure reveals a key substrate molecule bound to the protein cavity.
All organisms need energy but how this energy is generated at a molecular scale is not fully understood. A detailed comprehension of biological energy conversion is a prerequisite for the development of non-toxic environmentally friendly bio-batteries of the future. The pathway that generates energy in aerobic organisms is called respiratory chain, and dysfunction in this process by oxidative stress, point mutations, etc results in a number of diseases, for which treatment options are rather limited.
In this study, researchers from the Goethe University and the Max Planck Institute of Biophysics, Frankfurt, Germany, and the Department of Physics, University of Helsinki (UH), Finland studied one of the most complicated enzymes of the energy generating machinery. This enzyme, respiratory complex I, performs subtle electron and proton transfer reactions and contributes ca. 40-% of total biological energy generation in mitochondria.
By applying state-of-the-art cryo electron microscopy techniques, researchers from Max Planck Institute of Biophysics and Goethe University, Frankfurt solved the structure of complex I from Yarrowia lipolytica at a resolution of 3.2 Å. To investigate the dynamics of this intricate 1 mega Dalton protein complex, researchers from UH performed large-scale atomistic computer simulations of complex I by utilizing high-performance supercomputing platforms of the Center for Scientific Computing, Finland and Barcelona Supercomputing Center, Spain (PRACE – Partnership for Advanced Computing in Europe resources).
Remarkably, a substrate molecule (called ubiquinone that accepts or donates electrons in mitochondria) is observed in this new structure at a site which was earlier predicted based on molecular dynamics simulations, a physics-based approach to study dynamics of proteins. “Our joint efforts, combining structural biology with molecular simulation approaches, once again shows the importance of cross-disciplinary approaches in solving difficult biological questions. Moreover, the finding of a quinone molecule at the site predicted by our computer simulations earlier, very much strengthens the central role simulations play in studies of enzyme catalysis,” says Vivek Sharma, who led the simulation project at the Department of Physics, UH.
Kristian Parey, Outi Haapanen, Vivek Sharma, Harald Köfeler, Thomas Züllig, Simone Prinz, Karin Siegmund, Ilka Wittig, Deryck J. Mills, Janet Vonck, Werner Kühlbrandt and Volker Zickermann. High-resolution cryo-EM structures of respiratory complex I: Mechanism, assembly, and disease. Science Advances 11 Dec 2019.
Redox-coupled quinone dynamics in the respiratory complex I. PNAS Sep 2018.
Role of Second Quinone Binding Site in Proton Pumping by Respiratory Complex I. Front. Chem. Apr 2019.