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HEIndividual fellowship2023–2024

IntraMol · Intramolecular optical microscopy with sub-nm spatial resolution in single biomolecules and single-protein sequencing

Horizon Europe — Marie Skłodowska-Curie Actions

Duration
2023-01-01 → 2024-12-31
EU contribution
€173,847
Participants
1
Scheme
HORIZON-TMA-MSCA-PF-EF

Lines connect the coordinator with its partners.

Results in brief

Intramolecular optical microscopy with sub-nm spatial resolution in single biomolecules and single-protein sequencing

Advancements in biomedical research rely heavily on our ability to visualize biological structures at the smallest possible scale. Traditional optical microscopy is limited by the diffraction of light (approx. 200 nm), making it impossible to resolve molecular structures with atomic precision. Super-resolution microscopy can overcome this barrier but it is still limited to around 10-20 nm in resolution. This project overcomes that limitation by developing Ångström-resolution fluorescence microscopy (Resolution Enhancement by Sequential imaging - RESI), a revolutionary technique capable of visualizing biomolecular interactions at a scale previously thought unattainable. By achieving a localization precision of approximately 1 Ångström (0.1 nanometers), this technique enables researchers to directly observe molecular arrangements, protein interactions, and structural changes in biological systems with unprecedented clarity. Such insights have profound implications for drug discovery, disease diagnostics, and the development of targeted therapies.

Data: CORDIS, © European Union

Project objective

Fluorescence microscopy has witnessed a true resolution revolution in the past decades. The invention of methods circumventing the classical diffraction limit of ≈200 nm has allowed researchers – for the first time – to reach sub-diffraction resolution with optical fluorescence microscopy. With these so-called super-resolution techniques, processes within cells can be observed at thus far unprecedented spatial resolutions. However, while incumbent super-resolution approaches enable researchers to resolve intermolecular distances between e.g. protein molecules in small protein clusters, the final frontier in optical bioimaging to resolve intramolecular distances in the sub-nm regime for single molecules is still elusive. With this research proposal, I want to develop and apply a paradigm-shifting imaging technology that allows intramolecular optical microscopy with sub-nm spatial resolution in single biomolecules.To achieve this goal, I will combine DNA-Point Accumulation Imaging Nanoscale Topography (DNA-PAINT) with DNA Exchange to overcome the current limit of optical nanoscopy in terms of spatial resolution. To do so, I will build a microscope with ultra-high stability and sensitivity. The project is conceived as an integral approach including the design of optics, instrumentation, labelling probes and data analysis.Such a capability provided by the project IntraMol would be a game changer in fluorescence microscopy, as it could – for the first time – allow scientists to resolve intramolecular distances e.g. within single proteins, thus enabling structural biology studies and provide insights into conformations of proteins even enable single-molecule protein sequencing using optical microscopy in situ.

Original text from CORDIS.

Participants

  • MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV · MUNCHENCoordinatorGermany

Links

Data: CORDIS, © European Union