Molecule-spanning dynamics and allostery in a multi-domain protein

• Applicants: Professor Dr. Thorsten Hugel; Dr. Steffen Wolf
• Subject Area: Biophysics ; Theoretical Chemistry: Electronic Structure, Dynamics, Simulation
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 569868905

Protein dynamics have been investigated on a wide range of timescales. Often nano- and picosecond dynamics have been assigned to local fluctuations, which are well-separated from the timescales of global structural changes on the microsecond to second timescales. It is largely unknown how such fast (local) fluctuations can lead to slow global (allosteric) changes. Recently, fast molecule-spanning dynamics on the 100 ns timescale have been revealed in experiments, which have the potential to bridge the gap between both time- and length-scale domains. Here, we will use a combination of MD simulations and fluorescence correlations spectroscopy to investigate the propagation of (allosteric) signals on a molecular level and their emergence from local fluctuations. This includes determination of speed and mode of action, i.e., sequential or global signal propagation. Moreover, we will determine how interactors affect the fluctuations in allosteric sites and protein function. Therefore, we will not only quantify how structural, but also how dynamical properties are regulated by nucleotides, cochaperones, clients or drugs. The obtained data will also be a benchmark on how well MD simulations fit experimental data for large-scale dynamics of multi-domain proteins. Altogether, we will gain a molecular understanding of how fluctuations and their regulation determine global conformational changes and affect function in multi-domain proteins.

• DFG Programme: Research Grants