Conformational changes upon phosphorylation of proline rich region of tau(210-240) peptide using molecular dynamic simulation

Krishnendu Bera1, 2, Isabelle Landrieu3, Jozef Hritz1, 2

1CEITEC MU, Masaryk University, Kamenice 753/5, 625 00 Brno, Czech Republic.

2Department of Chemistry, Faculty of Science, Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic.

3Univ. Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, F-59000 Lille, France.

krishnendu39@gmail.com, jozef.hritz@ceitec.muni.cz


The conformational dynamics of intrinsically disordered proteins (IDPs) regulated by post-translational modifications (PTMs) such as phosphorylation is challenging to elucidate. A well-known IDP Tau is found hyper-phosphorylated in Alzheimer’s disease (AD) in humans [1]. The proline-rich motif of tau(210-240) peptide directly interacts with proteins such as BIN1, 14-3-3 etc. Microsecond time scale, all atoms molecular dynamic (MD) simulation studies have been performed for apo and four phosphorylated (212PThr, 217PThr, 231PThr, 235PSer) tau(210-240) peptide using three different temperature variants (278K, 298K and 310K) and two different force field parameters (AMBER99SB-ILDN and CHARMM36m) with TIP4PD water model as these force fields parameters combine with water model worked the better for IDPs found from our group previous studies [2, 3]. These four-phosphorylations cause increase in compactness of the peptide. The binding of associated proteins like BIN1 with tau may alter by the strong salt bridges, forming nearby lysine and arginine due to the phosphorylation [4]. Phosphorylation induces a strong structural transition, with tau(210-240) favouring a bent conformation. The MD simulation results were verified using NMR experimental parameters like chemical shift and 3J-coupling. The experimental part has been carried out by our collaborator Prof. Isabelle Landrieu.

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  1. Shimada, T., Fournier, A. E., & Yamagata, K. (2013). Neuroprotective function of 14-3-3 proteins in neurodegeneration. BioMed research international, 2013.
  2. Zapletal, V., Mládek, A., Melková, K., Louša, P., Nomilner, E., Jaseňáková, Z., ... & Hritz, J. (2020). Choice of force field for proteins containing structured and intrinsically disordered regions. Biophysical Journal, 118(7), 1621-1633.
  3. Pavlíková Přecechtělová, J., Mládek, A., Zapletal, V., & Hritz, J. (2019). Quantum Chemical Calculations of NMR Chemical Shifts in Phosphorylated Intrinsically Disordered Proteins. Journal of Chemical Theory and Computation, 15(10), 5642-5658.
  4. Chen, Y., Chen, X., Yao, Z., Shi, Y., Xiong, J., Zhou, J., ... & Huang, Y. (2019). 14-3-3/Tau interaction and Tau amyloidogenesis. Journal of Molecular Neuroscience, 68, 620-630.

Computational resources were supplied by the metacentrum and IT4 Innovations National Supercomputing Center (OPEN-17-7), project (e-INFRA CZ 90140 and LM2018140) provided within the program Projects of Large Research, Development and Innovations Infrastructures. KB and JH were also funded by the Ministry of Education, Youth, and Sport of the Czech Republic (MEYS CR), grant number LTAUSA18168 (Inter-Excellence Inter-Action), Czech Science Foundation [GF20-05789L] and European  Union Excellence Hub (101087124). KB is also supported by Brno Ph.D. Talent Scholarship – funded by the Brno City Municipality, Brno, Czech Republic.