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Disclosing the Mechanism of Spontaneous Aggregation and Template-Induced Misfolding of the Key Hexapeptide (PHF6) of Tau Protein Based on Molecular Dynamics Simulation
journal contribution
posted on 2019-11-12, 12:38 authored by Hongli Liu, Haiyang Zhong, Xuewei Liu, Shuangyan Zhou, Shuoyan Tan, Huanxiang Liu, Xiaojun YaoThe
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.