Atomistic insights into the structure of the mitochondrial complex I

High-resolution dynamic information obtained from computer simulations allowed researchers to identify molecular valves and new design features in proteins. Credit: University of Helsinki

Structural biology and computer simulations pave the way for a deeper understanding of the conversion of biological energy. The high-resolution structure and atomistic simulations allowed researchers to identify new features in one of the key enzymes that help generate energy in cells.

One of the most important biological processes is the production of energy (ATP) in the mitochondria of cells. The molecular understanding of this key metabolic pathway remains uncertain, despite its central importance in biomedical and energy sciences. In a new study, researchers provide a detailed atomic view of a key component of mitochondrial energy metabolism, the respiratory complex I.

The first enzyme in the electron transport chain of mitochondria, a pathway fueling ATP synthesis, is respiratory complex I. This enzyme significantly contributes to the generation of ATP and is a focal point of function and of mitochondrial dysfunction. Building on their previous collaborative collaborative studies (1,2,3), researchers from Goethe University (Frankfurt, Germany), the Max Planck Institute for Biophysics (Frankfurt, Germany) and the Department of Physics (University from Helsinki, Finland) have just provided the most detailed atomistic overview of the structure of Complex I, a high-resolution structure resolved at 2.1 Å.

The high-resolution structure of a membrane protein of this size (~ 1 mega Dalton) is a remarkable achievement in the field of membrane structural biology and mitochondrial biology. Researchers at Goethe University and the Max Planck Institute for Biophysics have applied advanced cryoelectron microscopy to resolve the positions of several protein-bound water molecules, which perform the proton transfer reactions necessary to convert l chemical energy in ATP.

Jonathan Lasham, PhD student in the Multiscale Modeling and Mitochondrial Protein Simulation Research Group at the University of Helsinki, performed large-scale molecular dynamics simulations of high-resolution structural data. These simulations revealed a tight coupling between protein hydration, conformational dynamics and protein charge state. Currently, such high resolution dynamic information can only be obtained by computer simulations; this allowed researchers to identify molecular valves and new design features in proteins, which are important to achieve high catalytic efficiency. Additional calculations and analyzes carried out by research assistant Amina Djurabekova and doctoral student Outi Haapanen from the same research group further consolidated the research results.

“This is another big step forward in our ongoing collaboration with German colleagues and in our understanding of biological energy production, in that respiratory complex I, a biomedically relevant enzyme, generates energy in the most efficient manner, ”said Vivek. Sharma, Sigrid Jusélius Senior researcher at the Department of Physics at the University of Helsinki and PI of the Multiscale Modeling and Simulation of Mitochondrial Proteins research group.

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More information:
Kristian Parey et al, Structure and High Resolution Dynamics of Mitochondrial Complex I – Overview of the Proton Pumping Mechanism, Scientists progress (2021). DOI: 10.1126 / sciadv.abj3221

Etienne Galemou Yoga et al, Mutations in a conserved loop in the PSST subunit of respiratory complex I affect ubiquinone binding and dynamics, Biochimica et Biophysica Acta (BBA) – Bioenergetics (2019). DOI: 10.1016 / j.bbabio.2019.06.006

Kristian Parey et al, High-resolution cryo-EM structures of respiratory complex I: mechanism, assembly and disease, Scientists progress (2019). DOI: 10.1126 / sciadv.aax9484

Etienne Galemou Yoga et al, Essential role of the accessory subunit LYRM6 in the mechanism of the mitochondrial complex I, Nature Communication (2020). DOI: 10.1038 / s41467-020-19778-7

Provided by the University of Helsinki

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