Misfolding and Self-Assembly Dynamics of Microtubule-Binding Repeats of the Alzheimer-Related Protein Tau

Abstract

Pathological aggregation of intrinsically disordered tau protein, driven by the interactions between microtubule-binding (MTB) domains, is associated with Alzheimer’s disease. The MTB domain contains either three or four repeats with sequence similarities. Compared to amyloid β, many aspects of the misfolding and aggregation mechanisms of tau are largely unknown. In this study, we systematically investigated the dynamics of monomer misfolding and dimerization of each MTB repeat using atomistic discrete molecular dynamic simulations. Our results revealed that all the four repeat monomers (R1–R4) were very dynamic, featuring frequent conformational conversion and lacking stable conformations. While R1, R2, and R4 monomers occasionally adopted partially helical conformations, R3 monomers frequently formed β-sheets. In dimerization simulations, R3 displayed the strongest aggregation propensity with high β-sheet contents, while R1 was the least prone to aggregation. The R2 and R4 dimers contained both helix and β-sheet structures. The β-sheets in R4 assemblies were dominant with β-hairpin conformation. In R2 and R3 dimers, intermolecular β-sheets were mainly driven by residues around the paired helical filament (PHF) regions. Residues around the PHF6* in R2 and PHF6 in R3 had significantly higher intermolecular contacts than other regions, suggesting that these residues play a key role in the amyloid aggregation of tau. Our results on the structural ensembles and early aggregation dynamics of each tau MTB repeat will help understand the nucleation and fibrillization of tau.

Molecular Dynamics Simulations of the Tau R3–R4 Domain Monomer in the Bulk Solution and at the Surface of a Lipid Bilayer Model

“…A full-length tau encoding 441 amino acids is composed of a projection domain followed by a microtubule-binding domain of four repeats (labeled R1–R4) and a basic C-terminal. Tau has been shown to fibrillize in vitro in the presence of polyanionic substances. , The domain repeat R1–R4 termed K18 and spanning residues 244–368 contains two hexapeptides called PHF6* (VQIINK, residues 275–280 in R2) and PHF6 (VQIVYK, residues 306–311 in R3) that are essential for amyloid formation. , Inhibitors targeting the PHF6 motif were shown to block fibrillation. , Numerous simulations with distinct protein representations explored the conformations of tau441, , K18, K19 (which contains R1, R3 and R4 repeats), , and R1–R4 monomers, , R1–R4 and R3–R4 dimers, and the PHF6 oligomer , in a pure buffer. These simulations show that full-length tau and tau fragments do not behave as a random coil and adopt locally many transient secondary structures.…”

Molecular Insights into the Self‐Assembly of Block Copolymer Suckerin Polypeptides into Nanoconfined β‐Sheets

“…[ 32–34 ] With significantly enhanced sampling efficiency, DMD simulations have been widely used by various groups in studying protein folding, amyloid aggregation, and nanoparticle–protein interactions. [ 35–37,42,43,71–73 ] The force field used in the simulations was based on the Medusa force field. [ 70,74 ] The continuous potential functions of bonded interactions (i.e., covalent bonds, bond angles, and dihedrals) and non‐bonded interactions (i.e., van der Waals and electrostatic terms) were replaced by a serial of step functions in the all‐atom Medusa force field.…”

“…[32][33][34] With significantly enhanced sampling efficiency, DMD simulations have been widely used by various groups in studying protein folding, amyloid aggregation, and nanoparticle-protein interactions. [35][36][37]42,43,[71][72][73] The force field used in the simulations was based on the Medusa force field. [70,74] The continuous potential functions of bonded interactions (i.e., covalent bonds, bond angles, and dihedrals) and non-bonded interactions (i.e., van der Waals and electrostatic terms) were replaced by a serial of step Including the number of simulated peptides (system), the temperature of each simulated system (temperature), the modular repeat used in each system (module), the number of independent trajectories for each molecular system performed (DMD run), the duration time of each DMD run (time), and the accumulative time of each molecular system (total time).…”

Exploring the misfolding and self-assembly mechanism of TTR (105–115) peptides by all-atom molecular dynamics simulation

“…If the distance between the heavy atoms of two discontinuous residues is ≤5.4 Å, a pairwise residue is considered as contact status. If two or more coherent residues in each chain adopt the β -Strand conformation, and at least two backbone hydrogen bonds are obtained among these residues ( He et al, 2021 ), we considered that two chains can form a β -Sheet. The cluster conformations are employed the gromos analysis method with a Cα Root Mean Square Deviation (Cα-RMSD) cutoff of 0.4 nm using all the residues.…”