Deciphering the Effect of Lysine Acetylation on the Misfolding and Aggregation of Human Tau Fragment 171IPAKTPPAPK180 Using Molecular Dynamic Simulation and the Markov State Model

Abstract

The formation of neurofibrillary tangles (NFT) with β-sheet-rich structure caused by abnormal aggregation of misfolded microtubule-associated protein Tau is a hallmark of tauopathies, including Alzheimer’s Disease. It has been reported that acetylation, especially K174 located in the proline-rich region, can largely promote Tau aggregation. So far, the mechanism of the abnormal acetylation of Tau that affects its misfolding and aggregation is still unclear. Therefore, revealing the effect of acetylation on Tau aggregation could help elucidate the pathogenic mechanism of tauopathies. In this study, molecular dynamics simulation combined with multiple computational analytical methods were performed to reveal the effect of K174 acetylation on the spontaneous aggregation of Tau peptide 171IPAKTPPAPK180, and the dimerization mechanism as an early stage of the spontaneous aggregation was further specifically analyzed by Markov state model (MSM) analysis. The results showed that both the actual acetylation and the mutation mimicking the acetylated state at K174 induced the aggregation of the studied Tau fragment; however, the effect of actual acetylation on the aggregation was more pronounced. In addition, acetylated K174 plays a major contributing role in forming and stabilizing the antiparallel β-sheet dimer by forming several hydrogen bonds and side chain van der Waals interactions with residues I171, P172, A173 and T175 of the corresponding chain. In brief, this study uncovered the underlying mechanism of Tau peptide aggregation in response to the lysine K174 acetylation, which can deepen our understanding on the pathogenesis of tauopathies.

Identification of Aggregation Mechanism of Acetylated PHF6* and PHF6 Tau Peptides Based on Molecular Dynamics Simulations and Markov State Modeling

“…Previously, the Amber ff99SB force field has been successfully employed in the folding and aggregation studies of aggregation-prone peptides. , In this study we used the updated version of Amber ff99SB force field that is the Amber ff14SB force field that is used to carry out the simulations. The Amber ff14SB is a continuing evolution of the Amber ff99SB force field which has been previously reported by several groups studying the aggregation of amyloid peptide, , while others specifically mentioned the suitability of Amber ff14SB and CHARMM36m for Tau hexapeptide PHF6 aggregation simulations . Amber 18 was used to carry out the REMD and all-atom simulations of the individual monomers and 16-chain systems immersed in cubic box of TIP3P solvent model and neutralized with sodium and chloride ions.…”

Palmitic Acid Induces Posttranslational Modifications of Tau Protein in Alzheimer’s Disease–Related Epitopes and Increases Intraneuronal Tau Levels

“…Phosphorylation is the main PTM found in NFTs [ 1 – 3 ], but tau acetylation at specific residues has also been detected in the brains of AD patients [ 4 ]. Specifically, acetylation at K280 and K174 favors tau phosphorylation, diminishes tau degradation, and increases tau toxicity [ 5 – 10 ]. Tau PTMs may involve complex signaling pathways that alter the balance between the activity of protein kinases and protein phosphatases as well as acetylases and deacetylases.…”

Investigating the Theranostic Potential of Graphene Quantum Dots in Alzheimer’s Disease

“…Although mechanistic insights are crude and lacking in experimental studies, previous in silico work, including molecular dynamics (MD) simulations, has proven to be a powerful tool in facilitating such discoveries. In particular, the development of enhanced sampling and analysis techniques enables the study of these systems, uncovering the mechanistic and kinetic importance of certain regions on Tau in the aggregation process, and guiding future therapeutic targets [15][16][17].…”