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From Sensitivity to Resolution: Transforming DNP MAS NMR of biosolids

Project description

Boosting molecular insight with NMR advances

Understanding the structure of biomolecules is essential for developing new therapies, yet standard nuclear magnetic resonance (NMR) spectroscopy, which reads signals from atomic nuclei in a magnetic field, often lacks the sensitivity required. Supported by the Marie Skłodowska-Curie Actions programme, the HiResProtDNP project seeks to overcome these limits using dynamic nuclear polarisation (DNP). By combining high-field DNP with fast Magic Angle Spinning, researchers aim to create improved sample preparations, labelling strategies, and advanced pulse sequences for sharper, clearer spectra. They will also map specific atomic positions, first testing on model crystals before moving to vaccines and protein fibrils. HiResProtDNP promises faster, more precise insights for structural biology, drug discovery, and materials science.

Objective

Dynamic nuclear polarisation (DNP) has recently emerged as a transformative technology to address the sensitivity limitation of Nuclear Magnetic Resonance (NMR) spectroscopy. In the solid-state, hyperpolarisation has the potential to reveal unique insight into the structure of complex biological assemblies such as amyloid fibrils, membrane-embedded proteins, virus capsids or plant cell walls. However, despite key pioneering studies, several challenges must be resolved before DNP Magic Angle Spinning (MAS) NMR can be widely adapted as a routine analytical approach for studying biomolecules. The primary bottleneck is the resolution of 13C and 15N DNP enhanced NMR spectra of solid-state biomolecules which is compromised by severe line broadening at the cryogenic temperatures at which DNP experiments are performed. The second limitation is the absence of robust site-specific assignment strategies. Leveraging progress in fast MAS and high-field DNP NMR systems, the project will focus on improving spectral resolution through the development of (i) new sample formulations and labeling strategies, (ii) advanced radio-frequency pulse sequences using unique instrumentation at the host laboratory, and (iii) innovative methods for site-specific assignment of backbone and side-chain resonances. These methods will first be tested on model microcrystalline samples, then applied to complex biological targets like vaccines and fibrillar assemblies. The proposed work is highly interdisciplinary, connecting biochemical techniques, spin physics, and physical chemistry, and will have a broad impact across fields including structural biology, pharmaceutical science, and materials science. The methods developed will streamline data collection in biomolecular NMR and push the boundaries of what is currently possible with hyperpolarisation today. The project will significantly advance both fundamental and applied research, benefiting large communities of chemists and biologists.

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Topic(s)

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HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships

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Call for proposal

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(opens in new window) HORIZON-MSCA-2024-PF-01

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Coordinator

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 242 260,56
Address
RUE MICHEL ANGE 3
75794 PARIS
France

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Ile-de-France Ile-de-France Paris
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Research Organisations
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