Nonequilibrium functional dynamics of proteins

• Applicants: Professor Dr. Gerhard Stock; Dr. Steffen Wolf
• Subject Area: Statistical Physics, Nonlinear Dynamics, Complex Systems, Soft and Fluid Matter, Biological Physics
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 431945604

The project "Nonequilibrium functional dynamics of proteins" by Wolf, Stock, and Godec is concerned with the binding and unbinding of ligands to proteins and the resulting ligand-induced conformation transitions in intramolecular signaling. To explore various nonequilibrium conditions –such as the perturbation by light, mechanical stress and ligand binding– nonequilibrium MD simulations of photoinduced conformational change as well as dissipation-corrected targeted MD (dcTMD) will be employed. dcTMD will be benchmarked against a newly available theory-internal protein-ligand reference system, to evaluate its capabilities and shortcomings in finding ligand diffusion pathways and intermediate binding sites. Moreover, we will use dcTMD to understand deviations in bath dynamics from the equilibrium imposed by external driving and how they manifest in changes in dissipation as well as in fluctuations. Understanding these effects is crucial not only for the applicability of dcTMD, but of rate prediction methods using nonequilibrium simulations in general. These extensions of dcTMD will be also important for projects P6 and P8 of the Research Unit. To further explore the role of contact clusters in protein allosteric communication, we will extend our previous analysis of the PDZ3 domain to a broader class of proteins, including the tetracycline repressor TetR and heat shock protein 90. For systems with allosteric transition times on the micro- to millisecond scale, we will construct low-dimensional biasing coordinates based on relevant contact clusters and apply enhanced sampling techniques such as dcTMD and metadynamics. On a more coarse-grained theoretical level, we will conduct full mechanical-response analyses using a nonlinear, reversibly dissociable elastic network model. This approach will enable us to examine key aspects of allosteric communication, including nonlinearity, directionality, and specificity, which is also studied in project P5. To facilitate the building of quantum-classical models of biomolecular energy flow in project P11, we will provide for all considered systems the time-dependent energy content of the protein residues. MD data of ligand unbinding and intramolecular signaling will be provided for projects P4 and P5, whose analysis in turn will drive our investigations.

• DFG Programme: Research Units
• Subproject of: FOR 5099: Reducing complexity of nonequilibrium systems
• Co-Investigator: Dr. Aljaz Godec