Unraveling the Influence of K280 Acetylation on the Conformational Features of Tau Core Fragment: A Molecular Dynamics Simulation Study

Abstract

Abnormal aggregation of the microtubule-associated protein Tau is closely associated with tauopathies, including Alzheimer’s disease and chronic traumatic encephalopathy. The hexapeptide 275VQIINK280 (PHF6*), a fibril-nucleating core motif of Tau, has been shown to play a vital role in the aggregation of Tau. Mounting experiment evidence demonstrated the acetylation of a single-lysine residue K280 in the PHF6* was a critical event for the formation of pathological Tau amyloid deposits. However, the underlying mechanisms by which K280 acetylation affects Tau aggregation at the atomic level remain elusive. In this work, we performed replica exchange molecular dynamics simulations to investigate the influence of acetylation of K280 on the aggregation of PHF6*. Our simulations show that acetylation of K280 not only enhances the self-assembly capability of PHF6* peptides but also increases the β-sheet structure propensity of the PHF6*. The inter-molecular interactions among PHF6* peptides are strengthened by the acetylation of K280, resulting in an increased ordered β-sheet-rich conformations of the PHF6* assemblies along with a decrease of the structural diversity. The residue-pairwise contact frequency analysis shows that K280 acetylation increases the interactions among the hydrophobic chemical groups from PHF6* peptides, which promotes the aggregation of PHF6*. This study offers mechanistic insights into the effects of acetylation on the aggregation of PHF6*, which will be helpful for an in-depth understanding of the relationship between acetylation and Tau aggregation at the molecular level.

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

“…To study the self-aggregation of PHF6 peptides and phosphorylated PHF6, we simulated two different systems: the wild-type PHF6 system (named PHF6 system) and the Y310 phosphorylated system (named Pho-PHF6 system). The amino acid sequence of PHF6 is 306 VQIVYK 311 , capped by the ACE (CH 3 CO) group at the N-terminus and the NH 2 group at the C-terminus as determined computationally 44 and experimentally. 45 We first constructed the fully extended peptide using the PyMol program and then performed a 50 ns MD simulation at 450 K in water to generate the initial coil conformations.…”

“…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 . 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.…”

“…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. REMD and MD simulations were performed in combination for a total of 38.8 μs.…”

Mechanistic insight into the disruption of Tau R3–R4 protofibrils by curcumin and epinephrine: an all-atom molecular dynamics study

“…Here, a contact is formed when the aliphatic carbon atoms of two atom sets come within 0.54 nm or any other atoms of two atom sets lie within 0.46 nm. 48,49 Two aromatic rings are considered to form p-p stacking when their centroid distance is within 0.65 nm. 50 We defined a cation-p interaction if the distance between the N atom in an NH 3 + group and the centroid of an aromatic ring is less than 0.6 nm.…”

“…70,71 It is suitable for studying the structural characteristics of intrinsically disordered protein (IDP) like Tau. In recent years, several computational studies utilize the advanced sampling methods to characterize the structural features and conformational properties of Tau, 48,72,73 which provide a comprehensive understanding of Tau aggregation at the atomic level. This journal is © the Owner Societies 2022…”