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Elongation of Ordered Peptide Aggregate of an Amyloidogenic Hexapeptide NFGAIL Observed in Molecular Dynamics Simulations with Explicit Solvent
journal contribution
posted on 2005-10-05, 00:00 authored by Chun Wu, Hongxing Lei, Yong DuanThe mechanisms by which amyloidogenic peptides and proteins form soluble toxic oligomers
remain elusive. We have studied the formation of partially ordered tetramers and well-ordered octamers of
an amyloidogenic hexapeptide NFGAIL (residues 22−27 of the human islet amyloid polypeptide) in our
previous work. Continuing the effort, we here probe the β-sheet elongation process by a combined total of
2.0 μs molecular dynamics simulations with explicit solvent. In a set of 10 simulations with the peptides
restrained to the extended conformation, we observed that the main growth mode was elongation along
the β-sheet hydrogen bonds through primarily a two-stage process. Driven by hydrophobic forces, the
peptides initially attached to the surface of the ordered oligomer, moved quickly to the β-sheet edges, and
formed stable β-sheet hydrogen bonds. Addition of peptides to the existing oligomer notably improved the
order of the peptide aggregate in which labile outer layer β-sheets were stabilized, which provides good
templates for further elongation. These simulations suggested that elongation along the β-sheet hydrogen
bonds occurs at the intermediate stage when low-weight oligomers start to form. We did not observe
significant preference toward either parallel or antiparallel β-sheets at the elongation stage for this peptide.
In another set of 10 unrestrained simulations, the dominant growth mode was disordered aggregation.
Taken together, these results offered a glimpse at the molecular events leading to the formation of ordered
and disordered low-weight oligomers.