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

Abstract

Pathological aggregation of essentially dissociative Transthyretin (TTR) monomers protein, driven by misfolded and self-interaction, is connected with Amyloid Transthyretin amyloidosis (ATTR) disease. The TTR monomers protein contains several fragments that tend to self-aggregate, such as residue 105–115 sequence [TTR (105–115)]. However, the misfolding and aggregation mechanisms of TTR are still unknown. In this study, we explored the misfolding and self-assembly of TTR (105–115) peptides by all-atom molecular dynamics simulation. Our results indicated that the conformation of the two-peptides appears unstable. In the tetramerization and hexamerization simulations, the results are reversed. When the number of peptides increases, the probability and the length of β-Sheet contents increase. Our results show that that the four- and six-peptides both can form β-Barrel intermediates and then aggregate into fibers. The critical nucleation for the formation of fibril should be larger than four-peptides. The interactions between hydrophobic residues I107-L111 play an important role in the formation of stable fibrils at an early stage. Our results on the structural ensembles and early aggregation dynamics of TTR (105–115) will be useful to comprehend the nucleation and fibrillization of TTR (105–115).

Structures and Dynamics of β-Rich Oligomers of ATTR (105–115) Assembly

“…Representative ATTR (105–115) conformations of the bilayer β-sheet and β-barrel from the cluster analysis of MD simulations for the 4-, 6-, and 8-peptide systems (Supporting Figures S4–S6, respectively) indicate that the overall probability of β-barrels (31.28%) is greater compared to bilayer β-sheets (17.83%). It has been reported that four and six peptides of ATTR (105–115) form β-barrel intermediates and subsequently aggregate into fibers …”

“…It has been reported that four and six peptides of ATTR (105−115) form β-barrel intermediates and subsequently aggregate into fibers. 30 Over time, snapshots of the 4-and 6-peptide bilayer and 8peptide monolayer at 100 ns intervals are presented in Figures S11, S12, and S13, respectively. It is evident that the 4-peptide bilayer is dominated by β-sheet conformations.…”

Metastable alpha‐rich and beta‐rich conformations of small Aβ42 peptide oligomers

“…The first reason comes from the high propensity of β-sheets revealed by oligomer simulations at a very high concentration of small fragments of Aβ (Aβ16-22, Aβ37-42, Aβ25-35, Aβ10-24 and Aβ35-40), tau (PHF6 motif, repeats R1-R4), transthyretin (105-115) and β2-microglobulin (83-89) peptides which also form fibrils. [29][30][31][32][33][34][35][36] It is notable, however, that two simulations on Aβ16-22 oligomers proposed helical intermediates. [37][38][39] Second, the preference for β-sheet formation comes from the fact that many computational methods do not explore the full conformational ensemble.…”