Disclosing the Mechanism of Spontaneous Aggregation and Template-Induced Misfolding of the Key Hexapeptide (PHF6) of Tau Protein Based on Molecular Dynamics Simulation

Abstract

The microtubule-associated protein tau is critical for the development and maintenance of the nervous system. Tau dysfunction is associated with a variety of neurodegenerative diseases called tauopathies, which are characterized by neurofibrillary tangles formed by abnormally aggregated tau protein. Studying the aggregation mechanism of tau protein is of great significance for elucidating the etiology of tauopathies. The hexapeptide 306VQIVYK311 (PHF6) of R3 has been shown to play a vital role in promoting tau aggregation. In this study, long-term all-atom molecular dynamics simulations in explicit solvent were performed to investigate the mechanisms of spontaneous aggregation and template-induced misfolding of PHF6, and the dimerization at the early stage of nucleation was further specifically analyzed by the Markov state model (MSM). Our results show that PHF6 can spontaneously aggregate to form multimers enriched with β-sheet structure and the β-sheets in multimers prefer to exist in a parallel way. It is observed that PHF6 monomer can be induced to form a β-sheet structure on either side of the template but in a different way. In detail, the β-sheet structure is easier to form on the left side but does not extend well, but on the right side, the monomer can form the extended β-sheet structure. Furthermore, MSM analysis shows that the formation of dimer mainly occurs in three steps. First, the separated monomers collide with each other at random orientations, and then a dimer with short β-sheet structure at the N-terminal forms; finally, β-sheets elongate to form an extended parallel β-sheet dimer. During these processes, multiple intermediate states are identified and multiple paths can form a parallel β-sheet dimer from the disordered coil structure. Moreover, the residues I308, V309, and Y310 play an essential role in the dimerization. In a word, our results uncover the aggregation and misfolding mechanism of PHF6 from the atomic level, which can provide useful theoretical guidance for rational design of effective therapeutic drugs against tauopathies.

Computer-Aided Drug Design of β-Secretase, γ-Secretase and Anti-Tau Inhibitors for the Discovery of Novel Alzheimer’s Therapeutics

“…The high flexibility of Tau makes it an attractive target for MD simulations, which is a very useful CADD technique for understanding the mechanism of Tau aggregation. All-atom MD simulations in explicit solvent were successful in investigating the mechanism of spontaneous Tau aggregation using PHF6 [161]. This study showed that PHF spontaneously aggregates to form multimers with β-sheet structure existing in a parallel arrangement.…”

“…It was also observed that PHF6 ( 306 VQIVYK 311 ) monomer can be induced to form a β-sheet structure on either side of the template with the left side to be formed more favorably but not be extended, while the right side can form an extended β-sheet structure. Residues Ile308, Val309, and Try310 were reported to play an essential role during the process of β-sheet dimerization from the disordered coil structure [161]. The misfolding mechanism of the Tau monomer upon induction of formed PHFs and SFs were uncovered with a combination of conventional and steered MD simulations [162].…”

Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

“…148 Numerous MD simulations have been conducted to study the PHP6 conformation and aggregation. In a recent MD and Markov state model (MSM) study, 151 PHF6 can spontaneously aggregate to form multimers enriched with β-sheet structure and the β-sheets in multimers prefer to exist in a parallel way. The residues Ile308, Val309, and Tyr310 play an essential role in the dimerization.…”

“…The separated monomers collide with each other at random orientations, then a dimer with short β-sheet structure at the N-terminal forms; finally, β-sheets elongate to form an extended parallel β-sheet. 151 Many studies have targeted these hexapeptide regions to prevent tau aggregation and toxicity. Using the model peptide, Ac-PHF6-NH2, the substitution of its amino acids with proline is shown to reduce self-assembly.…”

A mathematical model of heat shock response to study the competition between protein folding and aggregation

“…Such protein aggregation has been seen, for example, in β-lactoglobulin and its peptides when they spontaneously aggregate to form amyloid fibrils (25). Spontaneous aggregation also occurs in PHF6, a key hexapeptide of tau protein, the mechanism for which was shown in a recent molecular dynamics simulation study (26). In addition to such aggregation, proteins are also known to show hysterisis between unfolding and folding.…”