Development and application of solid-state NMR methodology to harness protons for the assessment of internal dynamics of proteins and bound ligands

• Applicant: Professor Rasmus Linser, Ph.D.
• Subject Area: Biophysics
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 580882727

Solid-state NMR spectroscopy has been instrumental for experimental access to internal dynamics of molecules of various kinds. For proteins, in particular, a large arsenal of methodology exists to decipher motional characteristics in highest detail. These methods tend to rely on isotope-labeled heteronuclei such as 15N and 13C, however, which effectively excludes the assessment of any embedded/associated pharmacological inhibitors, enzyme substrates/substrate mimics, secondary messengers, or other small-molecule or nucleic acid effectors, etc., which can rarely be provided in isotope-labeled fashion. Here, instead, we aim to provide quantitative access to site-specific dynamics exploiting protons as reporters. Apart from being ubiquitously abundant even in the mentioned protein ligands, they are bestowed with a series of unique spectroscopic prospects that have escaped practical exploration due to technical hurdles, such as strong coherent effects, till now. Based on state-of-the-art instrumentation, on major innovations in the applied spectroscopic and data processing approaches, as well as on highly promising preliminary data, we will systematically reshape the current technical framework to achieve quantitative, proton-derived access to atomic motion and harness unprecedented features of motion, such as spatial aspects of protein dynamics. The composed technical solutions, which we will showcase targeting ligand dynamics in an enzyme:inhibitor complex, will open the door to a completely new set of possibilities to decipher dynamics in biomolecules, including manifold targets that have been effectively inaccessible to-date, with a plethora of implications for downstream research such as pharmacology and biotechnology.

• DFG Programme: Research Grants