Multi-scale molecular simulations and artificial design of long-range conformational switches (B12*)

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Long-range conformational transitions modulate the activity of molecular chaperones, ion pumps, enzymes, and signalling proteins, but the mechanistic principles of this action-at-a-distance effect are poorly understood. In this project we employ multi-scale quantum and classical molecular simulation techniques to provide molecular insight into the structure, function, and dynamics of long-range conformational protein switches. We will study the heat shock protein (Hsp) 90 machinery, for which the molecular simulations are performed in close collaboration with the experimental groups within the CRC. We aim to elucidate how post-translation modifications, effector molecule binding, and protein dimerisation perturb the catalytic activity. To study the general long-range coupling principles, we design molecular switches in artificial helical bundle proteins, with an ultimate goal to design an electrostatic switch that can modulate an ATPase activity at large distances by conformational changes in arrays of charged residues within the bundle.