Molecular dynamics analyses of cross-beta-spine steric zipper models: beta-sheet twisting and aggregation

Abstract

The structural characterization of amyloid fibers is one of the most investigated areas in structural biology. The structural motif, denoted as steric zipper, recently discovered for the peptide GNNQQNY [Nelson, R., Sawaya, M. R., Balbirnie, M., Madsen, A. O., Riekel, C., Grothe, R. & Eisenberg, D. (2005) Nature 435, 773-778], is expected to exert strong influence in this field. To obtain further insights into the features of this unique structural motif, we report several molecular dynamics simulations of various GNNQQNY aggregates. Our analyses show that even pairs of beta-sheets composed of a limited number of beta-strands are stable in the 20-ns time interval considered, which suggests that steric zipper interactions at a beta-sheet-beta-sheet interface strongly contribute to the stability of these aggregates. Moreover, although the basic features of side chain-side chain interactions are preserved in the simulation, the backbone structure undergoes significant variations. Upon equilibration, a significant twist of the beta-strands that compose the beta-sheets is observed. These results demonstrate that the occurrence of steric zipper interactions is compatible with flat and twisted beta-sheets. Molecular dynamics simulations carried out on two pairs of beta-sheets, separated in the crystal state by a hydrated interface, lead to interesting results. The two pairs of sheets, while twisting, associate through stable peptide-peptide interactions. These findings provide insight into the mechanism that leads to the formation of higher aggregates. On these bases, it is possible to reconcile the crystallographic and the EM data on the size of the basic GNNQQNY fiber unit.

Fig. 1.

Two different views of the assembly of GNNQQNY molecules in the crystal state (Protein Data Bank code 1YJP) (14). (A) The parallel arrangement of the strands within the β-sheets. The side chains of residues pointing outward are colored black. Examples of polar zipper side chain–side chain hydrogen-bonding interactions also are shown. (B) The wet and dry interfaces are shown.

Fig. 2.

A representative example of SH2–ST4 structure in the equilibrated region of the trajectory. For clarity, only the C^α trace and the side chain atoms are shown. The model with the lowest rmsd compared with the average SH2–ST4 structure is shown.

Fig. 3.

A representative example of SH2–ST10 structure in the equilibrated region of the trajectory. For clarity, only the C^α trace and the side chain atoms are shown. The model with the lowest rmsd values compared with the average SH2–ST10 structure is shown.

Fig. 4.

A representative example of SH2–ST50 backbone structure in the equilibrated region of the trajectory. The pitch of the helical suprastructure of a single β-sheet also is shown.

Fig. 5.

rmsf values computed on side chain atoms of GNNQQNY residues in the 2,000- to 10,000-ps interval for the SH2–ST10 simulation. For Gly residues, the C^α atom was considered. Residues with side chains protruding toward the solvent or located in the dry interface are represented with squares and triangles, respectively. The residues of the two β-sheets span from 1–70 (SH1) and from 71–140 (SH2).

Fig. 6.

A representative example of SH4–ST10 structure in the equilibrated region of the trajectory. The different views of the model show the twisting of the sheets (A) and the novel, formed dry interface between the two pairs of sheets (B).

Fig. 7.

rmsf values computed on side chain atoms of GNNQQNY residues in the 2,000- to 10,000-ps interval for the SH4–ST10 simulation. For Gly residues the C^α atom was considered. Residues with side chains protruding toward the solvent or located in the dry interface are represented with squares and triangles, respectively. The residues of the four β-sheets span from 1–70 (SH1), 71–140 (SH2), 141–210 (SH3), and 211–280 (SH4).

Fig. 8.

The distance of interacting atoms in SH4–ST10 simulation plotted as a function of time. In particular, the following distances are shown: Tyr-98 O^η-Asn-164 N^δ2 (black), Gln-110 N^ε2-Gln-180 O^ε1 (gray), and Tyr-189 O^η-Asn-108 N^δ2 (light gray).