Secondary Structures Transition Of Intrinsically Disordered Protein Tau With Molecular Dynamics Simulation

Tau is one of the major pathophysiologically relevant protein in Alzheimer’s disease（AD）because the pathological Tau will aggregate into paired helical filaments（PHFs）and further causes progressive accumulation of neurofibrillary tangles（NFTs）.And the NFTs is one of the neuropathological hallmarks of the AD.Therefore,one of the top priorities in AD research is to figure out the structural model of Tau aggregation and to screen the inhibitors.On the other hand,molecular dynamics（MD）simulation is a powerful tool to investigate the dynamic ensemble of heterogeneous conformations and has referential significance to experiment for revealing the structure-function paradigm of IDPs.Force field plays a key role of MD simulations and the latest generation intrinsically disordered protein specific force field ff14IDPSFF significantly improved the distributions of heterogeneous conformations for intrinsically disordered proteins（IDPs）.Here,the molecular dynamics（MD）simulations with three force fields of ff14SB,ff14IDPs,and ff14IDPSFF were employed to investigate the secondary structures transition of Tau（267–312）fragment.The results indicate that ff14IDPSFF can generate more heterogeneous conformers,and the predicted secondary structural distribution is closer to that of the experimental observation.In addition,predicted secondary chemical shifts from ff14IDPSFF are the most approach to those of experiment.Secondary structures transition kinetics for Tau（267-312）with ff14IDPSFF shows that the secondary structures were gradually transformed from?-helix toβ-strand and theβ-strand located at the regions of the residues 274-280 and residues 305-311.Besides,the driving force for the secondary structures transition of Tau（267–312）is mainly hydrophobic interactions which located at hexa-peptides ²⁷⁵VQIINK²⁸⁰ and³⁰⁶VQIVYK³¹¹.Secondary structure transition of Tau protein can insight into the aggregation mechanism for AD.