Molecular Dynamics Simulation On The Misfolding Of HuPrP Key Fragments By Using Amyloidosis Fibers As Template

Conformational diseases are caused by the accumulation of unfolded or misfolded proteins. Previous studies suggested that these disorders were associated with the formation of amyloid fibrils. In this group, neurodegenerative diseases are studied deeply, whose amyloidosis are accompanied by the deposition of a specific aggregation-prone proteins and formation of insoluble fibrils. However, the misfolding structual feature and structural transition mechanism of protein are still unclear. Generally thinking, there are two possible mechanisms of protein misfolding: template assistance and seeding nucleation. Based on the hypothesis of template induced misfolding, we performed atomistic molecular dynamics simulations to explore if an disordered PrP(106-126) peptide would misfold in the presence of heterologous template Aβ(17-42) oligomer. By placing the unfolded PrP(106-126) monomer on the side of both the "odd end" and the "even end" of the Aβ pentamer, it is observed that the disordered monomer tured into the conformation with rich β-sheet in all of the six simulations. Two types of β-sheet pattern emerged:one-strand β-sheet and two-strand antiparallel β-sheets. And the two-strand β-sheets are more stable. We also find that besides the palindromic sequence (AGAAAAGA), the hydrophobic tail is also prone to form a β-sheet structure. Our study suggests that the transmission of protein misfoding by a prion-like mechanism might occur in the Aβ fibrils. In the second work, we performed atomistic molecular dynamics simulations to explore if an disordered PrP(98-110) peptide would misfold in the presence of the HET-s(218-289) trimer. There are only one type of β-sheet pattern emerged. And not all of the trajectories formed β-sheet pattern. The research on the mechanism of fibre growing showd that the growing of the fibre was triggered by the"docking"of the monomer on the fibre. This is consistent with the "dock-lock" mechanism. So, our research showed that the "cross-seeding" misfolding could happen on the amyloidosis peptide fragments. And it follows the "dock-lock"mechanism.