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Molecular dynamics simulation of the phosphorylation‐induced conformational changes of a tau peptide fragment
Author(s) -
Lyons Albert J.,
Gandhi Neha S.,
Mancera Ricardo L.
Publication year - 2014
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.24544
Subject(s) - phosphorylation , peptide , tau protein , biophysics , molecular dynamics , chemistry , microtubule , biochemistry , microbiology and biotechnology , biology , alzheimer's disease , medicine , computational chemistry , disease , pathology
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 (htau 225−250 ) 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 β‐sheet pattern ( 226 VAVVR 230 and 244 QTAPVP 249 ), 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 ( 239 AKSRLQT 245 ). PPII helical conformations were only found sporadically throughout the simulations. Proteins 2014; 82:1907–1923. © 2014 Wiley Periodicals, Inc.