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

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 β-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.

A Phosphorylation‐Induced Turn Defines the Alzheimer’s Disease AT8 Antibody Epitope on the Tau Protein

“…[17] We recently employed MD simulations to probe the structural role of phosphorylation on the AT180 epitope of the tau(208-324) fragment. [18] The secondary structures induced by phosphorylation of the pThr 231 and pSer 235 residues obtained from the simulations and from the corresponding NMR measurements were in good agreement. [19] By applying as imilar strategy,w e generated a1m st rajectory for peptide 1 with phosphorylations at Ser 202 and Thr 205 .I nc ontrast to what was found for other phosphorylated peptides of tau, [20] we observed no significant polyproline II (PPII) content in the secondary structure analyses of the trajectory ( Figure S4).…”

A Phosphorylation‐Induced Turn Defines the Alzheimer’s Disease AT8 Antibody Epitope on the Tau Protein

“…[8] Molecular dynamics (MD) simulations can be used to probe the structure and dynamics of partially folded or unfolded proteins with the trajectories validated using backcalculated NMR parameters. [18] The secondary structures induced by phosphorylation of the pThr 231 and pSer 235 residues obtained from the simulations and from the corresponding NMR measurements were in good agreement. [18] The secondary structures induced by phosphorylation of the pThr 231 and pSer 235 residues obtained from the simulations and from the corresponding NMR measurements were in good agreement.…”

A Novel Antibody Targeting Tau Phosphorylated at Serine 235 Detects Neurofibrillary Tangles

“…Furthermore, in vitro studies have demonstrated that phosphorylation of Ser235 abolishes the ability of tau to polymerize tubulin into microtubules [4], which could be due to disturbances in the local secondary structure of tau upon phosphorylation at this site [5,6]. An antibody specific for p-Ser235 may therefore be useful for the characterization of tau pathology.…”