Berlin 2024 – scientific programme
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BP: Fachverband Biologische Physik
BP 31: Protein Structure and Dynamics
BP 31.7: Talk
Thursday, March 21, 2024, 17:00–17:15, H 0112
Enzymatic phosphorylation of intrinsically disordered proteins in coarse-grained simulations — •Emanuele Zippo1, Lukas Stelzl1,2, Thomas Speck3, and Friederike Schmid1 — 1Institute of Physics, Johannes Gutenberg University Mainz, Mainz, Germany — 2Institute of Molecular Biology (IMB), Mainz, Germany — 3Institüt für Theoretische Physik IV, Universität Stuttgart, Stuttgart, Germany
Understanding the condensation and aggregation of intrinsically disordered proteins (IDPs) in a non-equilibrium environment is crucial for unraveling many biological mechanism. We can now address this with residue-level coarse-grained Molecular Dynamics simulations, integrating Metropolis Monte Carlo steps to model chemical reactions. We investigate TDP-43 phosphorylation by CK1d enzyme in simulations, examining patterns of phosphorylation and assessing its preventive role in chain aggregation, possibly associated with neurodegenerative diseases. We find that the degree of residue phosphorylation is determined by sequence preference and charges, rather than the position in the chain. Depending on the sequence context, phosphorylation stabilizes or de-stabilizes condensates. For TDP-43, our simulations show condensates dissolution through phosphorylation, in accordance with experiments. The disordered tail of the kinase Ck1d drives recruitment to the condensates. To further explore the dynamics of non-equilibrium steady-state systems, like our target system, we apply Markov state modelling (MSM). We used MSM to verify the thermodynamic consistency of the phosphorylation step.
Keywords: molecular dynamics; phosphorylation; liquid-liquid phase separation; non-equilibrium steady state; Markov state model