DYNAMOM · New magnetic resonance techniques to determine the dynamic structure of mitochondrial outer membrane proteins and their complexes

Membrane proteins are coded by about 30% of the genes in the human genome and are primary targets for the action of drugs. I propose an interdisciplinary approach that will provide insight into the dynamic structure of membrane proteins of the outer mitochondrial membrane at unprecedented detail with respect to spatial resolution and time scale separation. Analysis of the dynamics and structure of membrane proteins is one of the biggest challenges in structural biology. I propose several new techniques mainly for solution NMR spectroscopy but also for solid-state NMR and electron paramagnetic resonance that go far beyond the state of art and enrich the sparse information from each of the individual techniques. The integration of complementary experimental information together with molecular dynamics simulations will push the description of the dynamic structure of membrane proteins to a new level. This new level is characterized by the possibility to determine structural ensembles of higher structural complexity and by access to dynamic time scales ranging from picoseconds to milliseconds. The characterization of motion is expected to establish the essential link between structure and function. The chosen outer mitochondrial membrane proteins are linked to several human pathologies that cannot be treated because structural and dynamic information at atomic resolution is missing. I expect that the novel insight into the dynamic structure of mitochondrial proteins will be critical to lay the basis for the development of novel, selective and improved therapies for cancer and age-related neurodegeneration.