Nonequilibrium functional dynamics of proteins

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Biological processes in living organisms occur under inherent nonequilibrium conditions caused by concentration changes of substrates such as ATP, ions and ligands. As one consequence, drugs with slow unbinding kinetics require less frequent dosing and thus cause less side effects. Another process of interest is a protein’s own response to ligand binding or unbinding, which often amounts to allostery, i.e., correlated structural rearrangements between distant binding sites mediating inter- and intracellular signalling. Knowing the paths, dynamics and timescales of allosteric communication allows for the construction of small molecule drugs that inhibit such pathways by binding.Within the Research Unit "Reducing complexity of nonequilibrium systems", this project will extend and apply formal descriptions of nonequilibria and dynamical coarse-graining methods to biological systems to elucidate the molecular mechanisms determining timescales of protein-ligand (un)binding and the following responses of proteins. Since the conformational change depends on the binding mode of the ligand and conformational transitions may already occur during ligand (un)binding, both topics are closely related. We will mainly pursue dissipation-corrected targeted MD and temperature boosted Langevin simulations to describe the binding or unbinding of ligands to proteins, and coarse-grained Markov modeling to describe the subsequent conformational changes of proteins.