The Physical Driving Forces of Conformational Transition for TTR91–96 with Proline Mutations

Abstract

Pathological aggregation of essentially dissociated Transthyretin (TTR) monomer proteins, driven by misfolding and self-interaction, is associated with Transthyretin amyloidosis (ATTR) disease. The TTR monomer proteins consist of several fragments that tend to self-aggregate. Recent experimental studies showed that the sequence of residues TTR_91–96 plays an important role in self-aggregation. However, the mechanisms underlying the misfolding and aggregation of the TTR_91–96 monomers are still unknown. In this study, we used microsecond molecular dynamics simulations to investigate the misfolding and self-assembly of TTR_91–96 Octamers. We also investigated E92P and V94P mutants for comparative analysis. The analysis indicates that hydrophobic interactions and π–π stacking patterns play important roles in reducing the β-sheet content in the V94P and E92P mutants. Additionally, our findings reveal the conformational transition of TTR_91–96 octamer from closed β-barrel, open β-barrel to the β-bilayer aggregation. We further elucidate the dynamic mechanism of the transition from intermediate states to stable states. Overall, our research may contribute to the development of drug design to combat fibrous amyloid fibrous diseases.