Regensburg 2022 – wissenschaftliches Programm

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BP: Fachverband Biologische Physik

BP 7: Poster 1

BP 7.19: Poster

Montag, 5. September 2022, 18:00–20:00, P1

Time resolved signal propagation in a photoswitched PDZ3 domain — •Ahmed Ali, Adnan Gulzar, Steffen Wolf, and Gerhard Stock — Institute of Physics, University of Freiburg, Germany

Allostery is one of the most important mechanisms for biomolecular regulation. Generally, it involves a perturbation such as a binding event at one side of a macromolecule to affect another distant functional site. However, how such a perturbation propagates through the protein in detail is still not well understood. To establish a minimal allosteric model system, the third PDZ domain (PDZ3) of the postsynaptic density-95 (PSD-95) protein has been considered. The PDZ3 domain binds to the C-terminus of target proteins and regulates the signal propagation in PSD-95. In addition to the common and conserved central β-sheets and two α-helices present in all PDZ variants, PDZ3 contains a third C-terminal α-helix (α₃–helix) that packs against the β-sheet at a considerable distance to the ligand binding pocket.

In this work, we aim for a detailed understanding of the microscopic dynamics of allosteric communication between α₃ and the ligand binding pocket. In addition, we explicitly aim at finding intraprotein changes appearing on the same time scales as found in recent time-resolved IR spectroscopic experiments. Consequently, we perform direct nonequilibrium molecular dynamics (MD) simulations of PDZ3. We characterize the α₃-switched response by a combination of principal component analysis, clustering methods, and machine learning and characterize the microscopic mechanism behind the allosteric communication between α₃ and the ligand binding site.