Open Collections

Saali, Amirhossein

University of British Columbia

The aggregation of Aβ proteins into amyloid fibrillar structures, through various intermediate oligomeric forms and their deposition in the neocortex is the early event in the pathogenesis of Alzheimer’s disease. The formation of matured fibrils initiates from the formation of oligomeric structures at the early stages of fibrillation. However, due to the limitations of in vivo and in vitro experiments, the events at the early stages of aggregation are not clear. In this work, we studied the early aggregation mechanisms and possible structural transitions from the native  helix to the fibrillar β pleated sheet conformation. We did this by introducing additional hydrogen bond interactions to an existing implicit solvent force field to restrict the sampling of the conformational space of the protein to form the type of hydrogen bonds required to observe fibril-like structures. Firstly, the hydrogen bond-enhanced protein model was applied to a monomeric system to validate the model's performance and the system's stability. Next, the model was applied to a tetrameric system to determine possible structural transitions and aggregation to structures with high β-sheet content. The results are compared with the conventional implicit water model simulations and the relevant literature. Our observations show that the Aβ42 tetramer can form stable and β-sheet-enriched oligomeric structures through a two-step aggregation process, including the rapid accumulation of protein monomers and forming the initial β-sheet nuclei, followed by a time-consuming structural rearrangement. We found that the hydrophobic amino acid residues, especially the ones located in the C-terminus region of the Aβ42 protein, play a critical role in the formation and stability of β-sheet regions, which is consistent with the available experimental observations and theoretical expectations. More importantly, we were able to obtain four important sites, ALA-2, ILE-31, LEU-34, and MET-35, where the nucleation of β structures is more likely to initiate.

Text

2022-12-21

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/83451

Chemical and Biological Engineering

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/