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).