Insight into the stability of cross‐β amyloid fibril from molecular dynamics simulation

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). These methods can be used in stabilization study of other amyloid fibril. © 2010 Wiley Periodicals, Inc. Biopolymers 93: 578–586, 2010. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com