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    Molecular dynamics simulation of the phosphorylation-induced conformational changes of a tau peptide fragment

    213171_213171.pdf (634.5Kb)
    Access Status
    Open access
    Authors
    Lyons, Albert
    Gandhi, Neha
    Mancera, Ricardo
    Date
    2014
    Type
    Journal Article
    
    Metadata
    Show full item record
    Citation
    Lyons, A. and Gandhi, N. and Mancera, R. 2014. Molecular dynamics simulation of the phosphorylation-induced conformational changes of a tau peptide fragment. Proteins: Structure, Function and Bioinformatics. 82 (9): pp. 1907-1923.
    Source Title
    Proteins: Function, Structure, and Bioinformatics
    Additional URLs
    http://onlinelibrary.wiley.com/doi/10.1002/prot.24544/abstract
    ISSN
    10970134
    School
    School of Biomedical Sciences
    Remarks

    This is the accepted version of the following article: "Lyons, A. and Gandhi, N. and Mancera, R. 2014. Molecular dynamics simulation of the phosphorylation-induced conformational changes of a tau peptide fragment. Proteins: Structure, Function and Bioinformatics. 82 (9): pp. 1907-1923.", which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1002/prot.24544/abstract

    URI
    http://hdl.handle.net/20.500.11937/37474
    Collection
    • Curtin Research Publications
    Abstract

    Aggregation of the microtubule associated protein tau (MAPT) within neurons of the brain is the leading cause of tauopathies such as Alzheimer's disease. MAPT is a phospho-protein that is selectively phosphorylated by a number of kinases in vivo to perform its biological function. However, it may become pathogenically hyperphosphorylated, causing aggregation into paired helical filaments and neurofibrillary tangles. The phosphorylation induced conformational change on a peptide of MAPT (htau225-250) was investigated by performing molecular dynamics simulations with different phosphorylation patterns of the peptide (pThr231 and/or pSer235) in different simulation conditions to determine the effect of ionic strength and phosphate charge. All phosphorylation patterns were found to disrupt a nascent terminal ß-sheet pattern (226VAVVR230 and 244QTAPVP249), replacing it with a range of structures. The double pThr231/pSer235 phosphorylation pattern at experimental ionic strength resulted in the best agreement with NMR structural characterization, with the observation of a transient α-helix (239AKSRLQT245). PPII helical conformations were only found sporadically throughout the simulations.

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