Short peptide amyloid organization: stabilities and conformations of the islet amyloid peptide NFGAIL

Abstract

Experimentally, short peptides have been shown to form amyloids similar to those of their parent proteins. Consequently, they present useful systems for studies of amyloid conformation. Here we simulate extensively the NFGAIL peptide, derived from the human islet amyloid polypeptide (residues 22-27). We simulate different possible strand/sheet organizations, from dimers to nonamers. Our simulations indicate that the most stable conformation is an antiparallel strand orientation within the sheets and parallel between sheets. Consistent with the alanine mutagenesis, we find that the driving force is the hydrophobic effect. Whereas the NFGAIL forms stable oligomers, the NAGAIL oligomer is unstable, and disintegrates very quickly after the beginning of the simulation. The simulations further identify a minimal seed size. Combined with our previous simulations of the prion-derived AGAAAAGA peptide, AAAAAAAA, and the Alzheimer Abeta fragments 16-22, 24-36, 16-35, and 10-35, and the solid-state NMR data for Abeta fragments 16-22, 10-35, and 1-40, some insight into the length and the sequence matching effects may be obtained.

FIGURE 1

Schematic representation of the structural models that were built to search for the preferred arrangement for the hIAPP (22–27) peptide. Up to tetramers, strands of the same sheet are drawn with the same color. Schematic side-chain representations have been added to clarify the different possible orientations between chains of different β-sheets.

FIGURE 2

The main geometrical parameters used to describe the simulated molecular arrangements.

FIGURE 3

Some structural parameters used to characterize the organization of the NFGAIL segment within a sheet. The fraction of the initial hydrogen bonds for each model preserved along the simulation is presented for (a) dimers and (b) trimers. A hydrogen bond is considered when the O…H distance is less than 2.5 Å and the NH-O angle is larger than 130°. (c) The two mass center distances (d₁) and d_dtr (〈d₁〉) of trimer II. See Fig. 2 for definitions.

FIGURE 4

(a) The fraction of hydrogen bonds for each tetrameric model along the simulated time. (b) The average mass center distances (d₂) and the main strand distances 〈d_sh〉 (〈d₂〉) between sheets, for all tetramers investigated. (c) The average mass center distance (d₁) and the main strand distance 〈d_str〉 (〈d₁〉) within sheets, for all investigated tetramers. See Fig. 2 for definitions.

FIGURE 5

Detailed structural snapshots of all simulated tetramers, with equally spaced intervals over the 1 ns of the MD simulation. Strands that belong to the same sheet are drawn with the same color (either blue or red). Green balls show the N-terminus of each strand. Blue arrows point to positions of structural interest (see text).

FIGURE 6

(a) The fraction of hydrogen bonds for each hexamer for the three sheets along the simulation time. (b) The average mass center distances (d₂) and the main strand distances 〈d_sh〉 (〈d₂〉) between sheets, for all the models investigated. (c) The average mass center distance (d₁) and the main strand distance 〈d_str〉 (〈d₂〉) within sheets, for all models investigated. See Fig. 2 for definitions.

FIGURE 7

Detailed structural snapshots of the simulated hexamers with three sheets, with equally spaced intervals over the 1 ns of the MD simulation. Strands that belong to the same sheet are drawn with the same color (either blue or red). Green balls show the N-terminus of each strand. The blue arrow points to the position where the new sheet was added to the former tetramers.

FIGURE 8

Detailed structural snapshots of nonamers I and II, and the nonamer of the sequence NAGAIL, with equally spaced intervals over the 1 ns of the MD simulation. Strands that belong to the same sheet are drawn with the same color (either blue or red). Green balls show the N-terminus of each strand. Blue arrows point to the position of some structural rearrangements (see text).