Study of conformational changes of Tau(210-240) upon multiple
phosphorylations using molecular dynamics simulations

a 2023

Study of conformational changes of Tau(210-240) upon multiple phosphorylations using molecular dynamics simulations

BERA, Krishnendu and Thomas Peter FELLMETH

Basic information

Original name

Study of conformational changes of Tau(210-240) upon multiple phosphorylations using molecular dynamics simulations

Authors

BERA, Krishnendu and Thomas Peter FELLMETH

Edition

ITAT Conference, 2023

Other information

Language

English

Type of outcome

Konferenční abstrakt

Field of Study

10602 Biology , Evolutionary biology

Country of publisher

Slovakia

Confidentiality degree

není předmětem státního či obchodního tajemství

Organization unit

Central European Institute of Technology

ISBN

978-80-8147-132-2

Keywords in English

Molecular Dynamics, Tau, Intrinsically Disordered Protein

Změněno: 18/6/2024 12:03, Thomas Peter Fellmeth

Abstract

V originále

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

Links

MUNI/A/1414/2022, interní kód MU

Name: Specifický výzkum v oblasti „Life Sciences“

Investor: Masaryk University

Citovat

BERA, Krishnendu and Thomas Peter FELLMETH. Study of conformational changes of Tau(210-240) upon multiple phosphorylations using molecular dynamics simulations. In ITAT Conference. 2023. ISBN 978-80-8147-132-2.

@proceedings{2336517,
   author = {Bera, Krishnendu and Fellmeth, Thomas Peter},
   booktitle = {ITAT Conference},
   keywords = {Molecular Dynamics, Tau, Intrinsically Disordered Protein},
   language = {eng},
   isbn = {978-80-8147-132-2},
   title = {Study of conformational changes of Tau(210-240) upon multiple phosphorylations using molecular dynamics simulations},
   year = {2023}
}

TY  - CONF
ID  - 2336517
AU  - Bera, Krishnendu - Fellmeth, Thomas Peter
PY  - 2023
TI  - Study of conformational changes of Tau(210-240) upon multiple phosphorylations using molecular dynamics simulations
SN  - 9788081471322
KW  - Molecular Dynamics, Tau, Intrinsically Disordered Protein
N2  - 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
ER  -

BERA, Krishnendu and Thomas Peter FELLMETH. Study of conformational changes of Tau(210-240) upon multiple phosphorylations using molecular dynamics simulations. In \textit{ITAT Conference}. 2023. ISBN~978-80-8147-132-2.

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