Nucleation and growth of an amyloidogenic hexapeptide (NFGAIL) in aqueous solution observed in molecular dynamics simulations.

摘要

The formation and growth of ordered oligomers are perhaps the most crucial steps in amyloidogenesis, which are associated with many human diseases. In this work, molecular dynamics simulations with explicit solvent have been carried on systems containing 1--12 peptides to investigate the early-stage aggregation process of an amyloidogenic hexapeptide, NFGAIL (residues 22--27 of the human islet amyloid polypeptide). In the first study, a combined total of more than 600.0 ns simulation was conducted. Partially-ordered oligomers containing multistrand beta-sheets were observed which could be the precursory structures leading to the amyloid-forming embryonic nuclei. Of particular interest was the persistent fluctuation of the size of the aggregates throughout the simulations, suggesting that dissociation of peptides from the disordered aggregates was an obligatory step towards the formation of ordered oligomers. In second study, the nucleation of larger ordered-oligomers was further investigated by the simulations of a system containing 8 peptides that were constrained into 4 two-stranded beta-sheets A combined total of 960.0 ns simulations have been conducted on NFGAIL and its non-amyloidogenic mutant NAGAIL. It was found that the critical role played by the aromatic residue Phe was to direct the stacking of beta-sheets to form multi-layer ordered aggregates. In the third study, the nucleus growth stage was probed by a combined total of 2.0 mus simulations, in which four monomers were added into a water solution having a well-ordered seed. When constraining the peptides to extended conformation, the primary growth mode observed in the simulations was by beta-sheet extension, which followed two distinctive pathways: a one-step direct extension, and more often an indirect extension from rearranging the initially stacked peptides. The initial growth of the (disordered) aggregates was driven by hydrophobic interactions. In contrast, the beta-sheet extension was after the initial hydrophobic attachments and was well correlated with the formation of interstrand hydrogen bonds and interstrand polar-polar atom contacts, indicating beta-sheet extension was driven by electrostatic interactions. In comparison, a disordered growth was observed when not applying the constraints. Further analysis indicated that the disordered attachments were mainly caused by heterogeneous conformations of the peptide monomers.