Structural Analysis and Conformational Dynamics of Short Helical Hyperphosphorylated Segments of Tau Protein (Sequence 254–290) in Alzheimer’s Disease: A Molecular Dynamics Simulation Study

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder whose early diagnosis leads to a chance for successful treatment and decreases the side effects. Hyperphosphorylation of tau proteins is a pathological hallmark of AD that causes it to lose its attachment ability to the microtubules. Alteration of tau structure due to its hyperphosphorylation is an exciting challenge regarding AD treatments. Here, we aimed to examine the structural alterations of short helical segments of tau protein with one to three phosphorylated sites by molecular dynamics simulation. Results indicated that the interaction of two similar segments with three phosphorylated sites (P-Ser262, 285, and 289) formed a compact and more stable structure than the one phosphorylated site complex (P-Ser262). Moreover, due to the high dynamics of the P-Ser262 complex, several structures were made with different conformational dynamics, but there was only one stable cluster of the P-Ser262, 285, and 289 complex during simulation. It seems that the P-Ser262, 285, and 289 complex plays an important role in the formation of paired helical filaments (PHFs) by forming a stable dimer. Generally, it is important to identify how structural features of segments in tau protein change when the phosphorylated sites increase from one to three sites and their effects on the formation of PHFs for drug design and diagnostic biomarkers.

Atomistic Insights into the Inhibitory Mechanism of Tyrosine Phosphorylation against the Aggregation of Human Tau Fragment PHF6

“…By performing the combination of replica exchange MD (REMD) and MD simulations, Derreumaux et al examined the effect of phosphorylated Ser356 on the conformational ensemble of the tau R3–R4 domain dimer and reported that the R3–R4 dimer explored elongated, U-shaped, V-shaped, and globular forms; phosphorylation of Ser356 decreased the population of the β-helix motif spanning residues 336–354 and the intermediates near the fibril-like conformers . The MD simulation study on the tau K254–K290 fragment revealed that the complex with three phosphorylated sites (Ser262, 285, and 289) could form compact and more stable structures than that with one phosphorylated site (Ser262) . Our previous work investigated the influence of acetylation of K280 on the aggregation of PHF6* by performing REMD simulations and found that K280 acetylation strengthened the intermolecular interactions and led to more ordered β-sheet-rich structures .…”

“…42 The MD simulation study on the tau K254−K290 fragment revealed that the complex with three phosphorylated sites (Ser262, 285, and 289) could form compact and more stable structures than that with one phosphorylated site (Ser262). 43 Our previous work investigated the influence of acetylation of K280 on the aggregation of PHF6* by performing REMD simulations and found that K280 acetylation strengthened the intermolecular interactions and led to more ordered β-sheet-rich structures. 44 In this study, we focused on the early aggregation process of PHF6 peptides and explored the potential effect of the phosphorylation of Y310 on the PHF6 oligomerization.…”