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

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).