Secondary structures transition of tau protein with intrinsically disordered proteins specific force field

Abstract

Microtubule-associated Tau protein plays a key role in assembling microtubule and modulating the functional organization of the neuron and developing axonal morphology, growth, and polarity. The pathological Tau can aggregate into cross-beta amyloid as one of the hallmarks for Alzheimer's disease (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. 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 α-helix to β-strand and the β-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 275 VQIINK 280 and 306 VQIVYK 311 . Secondary structure transition of Tau protein can give insight into the aggregation mechanism for AD. K E Y W O R D Sff14IDPSFF force field, intrinsically disordered protein, secondary chemical shift, secondary structure transition, Tau protein

Molecular dynamics simulations of an α-synuclein NAC domain fragment with a ff14IDPSFF IDP-specific force field suggest β-sheet intermediate states of fibrillation

“…Indeed, it is in line with previous studies, which report that a promising feature of the ff14IDPSFF force field is the improved prediction of chemical shifts compared to ff14SB. 34,59,61,62 Our results using the IDPspecific force field together with the conformational analysis of previous studies and contrasted with the NMR experimental data point to a great success in exploring the aS conformational space within affordable MD simulation time lengths.…”

“…After studying short peptides and RNA-binding protein HIV-1 Rev, Duong et al 59 concluded that the ff14IDPSFF force field promotes random coil conformations and disordered secondary structures, which is consistent with experiments. An example of the capability of this force field is the studies of Song et al 34 and Dan et al , 61 in which the simulation of the all-atom microtubule-associated Tau protein with ff14IDPSFF is able to capture β-sheet conformations that are also observed in experiments. In a comparative study between force fields, the β-hairpin was found in conformational ensembles of β-amyloid proteins using IDP-specific force fields.…”

Effect of Natural Osmolytes on Recombinant Tau Monomer: Propensity of Oligomerization and Aggregation

“…61 Tau protein is an intrinsically disordered protein (IDP) in solution and adopts dynamic conformations in different conditions ending up with transient secondary structures rich in β-sheets. 62,63 Far UV-CD spectra of tauM incubated in PBS and with different osmolytes are illustrated in Figure 3A. Presence of a negative peak near 195−200 nm is an indication of the prevalent random coil structures.…”

Atomic Level Investigations of Early Aggregation of Tau43 in Water I. Conformational Propensity of Monomeric Tau43

“…In recent times, molecular dynamics (MD) simulations (often in conjunction with experiments) have significantly contributed in knowing the unknown aspects of Tau 24–35 . The PHF6 has been found to be stronger in aggregation propensity over PHF6* ( 275 VQIINK 280 , another PHF forming segment in hTau40), 24,32 and corresponding stability of the oligomers were controlled by hydrophobic and polar interactions 31 .…”

“…Other noted observations were conformational consequences of Tau hyper‐phosphorylation and exposure to osmolytes, 30,35 and domains responsible for hybrid Tau‐amyloid formations 27 . Further, comparative force field studies in better prediction of PHF6 have also been undertaken 26 . A generic observation from many of these studies is the importance of PHF6 in amyloid aggregation of Tau.…”