Amyloid-like fibrils had been associated with many fatal diseases, and the rational design of the fibrillization inhibitors holds the great promise of finding the prevention and treatment options. The understanding of the mechanisms by which the small molecules can inhibit the aggregation plays the key role in such design. Here we present the results of MD simulations that provide the atomistic details of the process, by which the small molecules may destabilize the ordered amyloid oligomers formed by the model hexapeptide. We select a heptapeptide fragment (GNNQQNY) from Sup-35 yeast prion protein, which is capable to form both amyloid fibrils and microcrystals. Atomic-resolution structures of its crystals were reported by Eisenberg et al. (Nature 447:453, 2007). We analyze several MD trajectories describing the evolution of the decamer fragment taken from this crystal structure, both by itself and in the presence of myricetin and kaempferol (two naturally occurring polyphenols, found to be strong and weak aggregation inhibitors). While the decamer of GNNQQNY demonstrates remarkable stability of its structure after 2ns simulation, myricretin disturbs the aggregation. The simulations show myricetin interacts with the beta-sheet due to polar interactions with side chains of the peptide weakening the interstrand hydrogen bonds, wrapping the beta-sheet and disaggregating the outer layer. Both backbone to backbone and side chain to side chain hydrogen bonds are lost, and the beta-sheets are moving away from each other. This leads to the loss of backbone H-bonding and eventual separation of one beta-strands from the outer layer. We also test several AMBER force fields and implicit solvent models for their ability to keep the decamer of GNNQQNY aggregated. The RMSDs of decamer of GNNQQNY with force field 99SB and implicit solvent models of igb2 and igb5, were maintained at less than 4A.

• PMID: 20456856
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Journal Article | Research Support, U.S. Gov't, Non-P.H.S.

Authors

Berhanu WM, Masunov AE

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