Berlin 2024 – scientific programme

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BP: Fachverband Biologische Physik

BP 10: Computational Biophysics II

BP 10.6: Talk

Tuesday, March 19, 2024, 10:45–11:00, H 0112

Allosteric communication in PDZ3 studied by nonequilibrium simulations and Markov State Model — •Ahmed Ali, Adnan Gulzar, Steffen Wolf, and Gerhard Stock — Institute of Physics, University of Freiburg, Germany

While allostery is of paramount importance for protein signaling and regulation, the underlying dynamical process of allosteric communication is not well understood. PDZ3 domain represents a prime example of an allosteric single-domain protein, as it features a well-established long-range coupling between the C-terminal α3-helix and ligand binding. In an intriguing experiment, Hamm and coworkers employed photoswitching of the α3-helix to initiate a conformational change of PDZ3 that propagates from the C-terminus to the bound ligand within 200 ns. Performing extensive nonequilibrium molecular dynamics simulations combined with Markov modeling, the modeling of the experiment reproduces the measured timescales and reveals a detailed picture of the allosteric communication in PDZ3. In particular, a correlation analysis identifies a network of contacts connecting the α3-helix and the core of the protein, which move in a concerted manner. Representing a one-step process and involving direct α3-ligand contacts, this cooperative transition is considered as elementary step in the propagation of conformational change.

Keywords: Allostery; nonequilibrium simulation; Markov State Model