| Description |
It is challenging to elucidate the conformational dynamics of intrinsically disordered proteins (IDPs) regulated by post-translational modifications (PTMs) such as phosphorylation. Tau is a well-known IDP, found hyperphosphorylated in Alzheimer’s disease (AD) in humans [3]. The proline-rich domain of tau directly interacts with its partner proteins such as BIN1, 14-3-3 etc. All atoms molecular dynamic (MD) simulation studies have been performed in microsecond time scale for wildtype and four phosphorylated(pT212, pT217, pT231, pS235) tau(210-240) peptide using three different temperatures (278K, 298K and 310K) and two different force field parameters (AMBER99SB-ILDN and CHARMM36m) with TIP4PD water model as combination of these parameters worked the better for IDPs found from our group previous studies [4, 2]. These four-phosphorylations cause increase in compactness of the peptide resulting bent conformation. From the experimental studies we found the binding affinity reduced by 12-folds between SH3 domain of BIN1 protein and tau(210-240). 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 [1]. Phosphorylation induces a strong structural transition, with tau(210-240) favouring a bent conformation. Currently we are testing the coarse grain force fields. The MD simulation results were verified using NMR experimental parameters like chemical shift and 3J-coupling [1]. References: [1] A. Lasorsa, K. Bera, Idir Malki, Elian Dupre, F.-X. Cantrelle, H. Merzougui, D. Sinnaeve, X. Hanoulle, J. Hritz, and I. Landrieu. Conformation and affinity modulations by multiple phosphorylation occurring in the bin1 sh3 domain binding site of the tau protein proline-rich region. Biochemistry, 62(11):1631–1642, 2023. [2] E. Lucendo, M. Sancho, F. Lolicato, M. Javanainen, W. Kulig, D. Leiva, G. Duarte, V. Andreu-Fernandez, I. Mingarroe, and M. Orzaez. Mcl-1 and bok trans-membrane domains: Unexpected players in the modulation of apoptosis. PNAS, 117(1):27980–27988, 2020. [3] T. Shimada, A. E. Fournier, and K. Yamagata. Neuroprotective function of 14-3-3 proteins in neurodegeneration. BioMed research international, 2013. [4] V. Zapletal, A. Mladek, K. Melkova, P. Lousa, E. Nomilner, Z. Jasenakova, V. Kuban, M. Makovicka, Lanikova, L. Zidek L, and J. Hritz. Choice of force field for proteins containing structured and intrinsically disordered regions. Biophys J, 118(7):1621–1633, 20
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