Recent evidence suggests that amyloidogenic oligomers may be the toxic species in cell cultures. Thus, it is crucial to understand their structure and oligomerization mechanism in atomistic detail. By employing tens of fast central processing units and an advanced phase-space sampling algorithm, parallel-tempering molecular dynamics, we have explored the energy landscape of amyloidogenic peptide oligomerization in explicit water. A pentapeptide, DFNKF, derived from human calcitonin and its mutant, DFAKF, was simulated with a total simulation time of ≈500 ns. The detailed oligomerization process of a DFNKF parallel β-sheet formation at 300 K has been characterized. The assembly of a parallel β-sheet from the amorphous state mainly occurs via a "bottleneck" channel where the interstrand Asn-Asn stacking is the major interaction. The interactions of Asn-Asn stacking include both backbone and side-chain hydrogen bonds. The Asn-Asn interactions work like "glue" by sticking the DFNKF strands together and assist the "on-pathway" oligomerization. The Asn-Asn stacking observed here is similar to the Asn ladder commonly found in globular β-helix proteins. A control run shows that when Asn is mutated to Ala, the stability and population of the DFAKF parallel β-sheet is decreased. Furthermore, our in vitro mutagenesis experiments show that the ability of DFAKF peptides to form amyloid fibrils is significantly reduced, in agreement with the simulations. Knowledge of the energy landscape of oligomerization may provide hints for rational drug design, preventing amyloid-associated diseases.
|Number of pages||6|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - 7 Jun 2005|
- Amyloid oligomerization
- Bottleneck channel
- Human calcitonin