Theoretical Research Of The Misfolding Mechanism Of Amyloid Fibril

Amyloid fibrils are considered to play causal roles in the pathogenesis of amyloid-related degenerative diseases such as Alzheimer's disease, type II diabetes mellitus, the transmissible spongiform encephalopathies, and prion disease. The mechanism of fibril formation is still hotly debated and remains an important open question.In this study, we utilized molecular dynamics (MD) simulation to analyze the stability of hexamer for eight class peptides. The MD results suggest that VEALYL and MVGGVV-1 are the most stable ones, then SNQNNY, followed by LYQLEN, MVGGVV-2, VQIVYK, SSTSAA, and GGVVIA. The statistics result indicates that hydrophobic residues play a key role in stabilizing the zipper interface. Single point and two linkage mutants of MVGGVV-1 confirmed that both Met1 and Val2 are key hydrophobic residues. This is consistent with the statistics analysis. The stability results of oligomer for MVGGVV-1 suggest that the intermediate state should be trimer (3-0) and tetramer (2-2).Furthermore, we study the stability of VEALYL. Single point and two linkage mutants suggest that Val1 are key hydrophobic residue for VEALYL. The stability results of oligomer for VEALYL showed that trimer (3-0) is the most possible intermediate state. Therefore, the most possible intermediate state of amyloid fibril might be trimer (3-0). These results play key role in understanding the aggregation mechanism of amyloid. These methods can be used in stabilization study of other amyloid fibril.