Spin-based Quantum Light Microscopy (SQLM) in Chemical Biology

• Subject Area: Physical Chemistry of Molecules, Liquids and Interfaces, Biophysical Chemistry
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 491319167

This project proposes to apply SQLM in Chemical Biology and push the domain of molecular spectroscopy for structural biology and biophysics into the living cell. Current characterization methods for structure and dynamics of proteins are generally applied in vitro. In the cell, posttranslational modifications, crowding effects, non-specific or specific interactions with cellular components and in particular organelle specific localization significantly affect structure and conformational equilibria of proteins. Non-invasive methods to probe protein structures at the molecular level, especially, when combined with high spatial resolution in the cell, are essential for unravelling one of the most challenging research questions in Chemical Biology - the complex physical mechanism of life. Magnetic resonance spectroscopy and optical microscopy are key technologies in the life sciences. While magnetic resonance is essential in revealing the structure, dynamics, and function of biomolecules, light microscopy is a key tool in cell biology whose principal benefit is to provide information about the location of macromolecules. In this project, we will combine both approaches in SQLM. Simultaneous monitoring of structure, dynamics, interactions and localization of proteins in the living cell is the challenging ultimate goal of the proposed project. We want to further develop and apply room-temperature SQLM for studying structure and dynamics of proteins under conditions with increasing complexity. In order to study endogenous, naturally translated and processed proteins directly in their natural host cells, we will develop and apply tailored strategies for labelling in vivo.Involving physicists, chemists, and biologists, we will establish a new core facility SQLM at the University of Konstanz supporting its research priority Chemical Biology, in particular the research areas Chemical and Biological Principles of Cellular Proteostasis as well as MolecularProcesses in Cellular Adaptation. We have identified seven projects to address research questions like:“How does folding of intrinsically disordered proteins depend on their localization in the cell?”“How do molecular chaperones promote proper folding of other proteins in vivo?”“How do misfolded or damaged proteins lead to neurodegenerative diseases?”SQLM in living cells in combination with in vivo labelling strategies will boost our understanding of proteostasis and cellular adaptation far beyond the current state of knowledge in a unique way by working as a “Microscope for protein structures”.We will demonstrate that novel SQLM approaches will open up possibilities to explore key aspects of the complex mechanisms of life at the molecular level in cellula, which have hitherto been unachievable.

• DFG Programme: Major Instrumentation Initiatives
• Major Instrumentation: SQLM
• Instrumentation Group: 5040 Spezielle Mikroskope (außer 500-503)
• Applicant Institution: Universität Konstanz
• Leader: Professor Dr. Malte Drescher