The misfolding mechanism of the key fragment R3 of tau protein: a combined molecular dynamics simulation and Markov state model study

Abstract

All-atom molecular dynamics (MD) simulation combined with Markov state model (MSM) were used to uncover the structural characteristics and misfolding mechanism of the key R3 fragment of tau protein at the atomic level.

Intrinsic Origin of Tau Protein Aggregation: Effects of Histidine Tautomerism on Tau267–312 Monomer

“…After careful evaluation of convergence, the probability distributions of the α-helix and β-sheet content were found to be dissimilar (Figure A) for four tautomeric isomers, indicating that different neutral histidine tautomeric conditions (ε or δ) at positions 268 and 299 can affect the organizational and aggregation features of the tau monomer. The conformational change of tau from the native disorder state to the β-sheet rich structure is the significant feature of the production of tau fibrils . Thus, exploring the formation mechanism of the tau β-sheet rich structure is important to understand the pathogenic mechanism of different tauopathies.…”

“…Furthermore, within εε, εδ, and δε isomers, α-helices can be formed mostly at K14–V21 (content: 40–84%), K14–leucine (L18) (content: 45–85%), and K14–Q22 (content: 29–56%; Figure D). Overall, owing to high β-sheet secondary structure content, isomer δδ may play a supreme role in tau fibrilization and/or aggregation because the β-sheet content is the primary component that produces tau fibrils. , …”

“…The conformational change of tau from the native disorder state to the βsheet rich structure is the significant feature of the production of tau fibrils. 47 Thus, exploring the formation mechanism of the tau β-sheet rich structure is important to understand the pathogenic mechanism of different tauopathies. Particularly, as the essential secondary structural properties, the β-sheet content of δδ (26.2%) is higher than that of other isomers.…”

“…Overall, owing to high β-sheet secondary structure content, isomer δδ may play a supreme role in tau fibrilization and/or aggregation because the β-sheet content is the primary component that produces tau fibrils. 47,50 To obtain insight into the equilibration ensembles, RMSDbased structural cluster analysis was conducted using a hierarchical agglomerative method with an RMSD cutoff of 5.0 Å. The representative conformations of the top five clusters and their probabilities are shown in Figure 3.…”

Histidine Tautomeric Effect on the Key Fragment R3 of Tau Protein from Atomistic Simulations

“…Previous research suggested that the conformation of tau monomer may play an important role in the NFTs formation process, especially in the initial stage. 10 More recently, Mirbaha et al classified the conformations of tau monomer into two general categories: inert (M i ) monomer and seed-competent (M s ) monomer. 11 Differing from M i , M s indicates a tendency of self-aggregation and seeding activity.…”