| 摘要: | Prion proteins are associated with a group of transmissible neurodegenerative disorders such as scrapie in sheep and Creutzfeldt–Jakob disease in humans. Previous studies have shown that the C-terminal side of α-helix 2 of the prion protein undergoes a conformational change to the β-sheet form, which is the infectious isoform causing scrapie. However, information about the three-dimensional structure of the prion β-sheet is still lacking. As the α-helix 2 displays “chameleon” conformational behavior, gathering several disease-associated point mutations, it can be toxic to neuronal cells. This makes it a very important focus for research into the folding mechanics of PrPC. The purpose of this study was to investigate the differences in folding mechanics between prion fragment α-helix 2 and prion fragment β-sheet 2, and to use a steered molecular dynamics approach to infer which events are important to achieve a normal α-helix 2 peptide. Based on our simulations, we suggest that 2 conformational barriers, comprising 4 intramolecular hydrogen bonds (the 8th, 9th, 10th, and 11th) and 6 residues (Thr183, Ile184, Lys185, His187, Thr188, and Val189), might play important roles in the folding mechanics of α-helix 2 and that a lack of these events might cause its misfolding. Steered molecular dynamics simulations were carried out on the folding mechanics of protein α-helix 2. The hypothesis we propose is that 6 residues (Thr183, Ile184, Lys185, His187, Thr188, and Val189) are important in the correct folding of prion α-helix 2 |
