Insights into structure, stability, and toxicity of monomeric and aggregated polyglutamine models from molecular dynamics simulations

Abstract

Nine genetically inherited neurodegenerative diseases are linked to abnormal expansions of a polyglutamine (polyQ) encoding region. Over the years, several structural models for polyQ regions have been proposed and confuted. The cross-beta-spine steric zipper motif, identified recently for the GNNQQNY peptide, represents an attractive model for amyloid fibers formed by polyQ fragments. Here we report a detailed molecular dynamics investigation of polyQ models assembled by cross-beta-spine steric zipper motifs. Our simulations indicate clearly that these assemblies are very stable. Glutamine side chains contribute strongly to the overall stability of the models by fitting perfectly within the zipper. In contrast to GNNQQNY zipper motifs, hydrogen bonding interactions provide a significant contribution to the overall stability of polyQ models. Molecular dynamics simulations carried out on monomeric polyQ forms (composed by 40-60 residues) show clearly that they can also assume structures stabilized by steric zipper motifs. Based on these findings, we build monomeric polyQ models that can explain recent data on the toxicity exerted by these species. In a more general context, our data suggests that polyQ models with interdigitated side chains can provide a structural rationale to several literature experiments on polyQ formation, stability, and toxicity.

FIGURE 1

Intersheet distances of representative (A) htPSH2-ST4-Q15, (B) hhPSH2-ST4-Q15, and (C) ASH2-ST4-Q15 structures. The C^α-C^α distances and the hydrogen bonding interaction between the side-chain N^ɛ2 atom and the main-chain O atom of two facing Gln residues are shown in black and gray, respectively.

FIGURE 2

Average models for (A) htPSH2-ST4-Q15, (B) hhPSH2-ST4-Q15, and (C) ASH2-ST4-Q15.

FIGURE 3

Root mean-square fluctuation of Gln side chains in (A) htPSH2-ST4-Q15, (B) hhPSH2-ST4-Q15, and (C) ASH2-ST4-Q15. In both cases, the equilibrated region of the trajectory (2000–20,000 ps) was considered.

FIGURE 4

Transient interactions in the reversible local unfolding of htPSH2-ST4-Q15 at 500 K. (A) Reports the evolution of representative intersheet distances. The C^α-C^α distances and potential hydrogen bonding interactions between side chain–main chain atoms and side chain-side chain atoms of two facing Gln residues are shown in black, red, and green, respectively. (B) A snapshot on the first 1250 ps of simulation is presented. (C–E) Representative structures along the trajectory and hydrogen bonding interactions in yellow. For clarity, N, C, and O backbone atoms have been omitted.

FIGURE 5

Average model of htPSH4-ST4-Q15 derived from the MD trajectory (2000–10,000 ps). The RMSD of structures of the trajectory versus the starting model is reported in the inset.

FIGURE 6

Average model of ASH2-ST10-Q6 derived from the MD trajectory (2000–10,000 ps). The left and right insets report the starting model and the RMSD values of the structure of the trajectory, respectively.

FIGURE 7

Two different views of Q57 average model derived from the MD trajectory (5000–50,000 ps). The RMSD of structures of the trajectory versus the starting model (left) and the evolution of the secondary structure elements (right) are reported in the insets.

FIGURE 8

MD simulation of the model Q57: evolution of C^α–C^α distances (black) and main-chain side-chain H-bonding interactions (shaded) between representative facing Gln residues in the steric zipper interface.

FIGURE 9

Two different views of Q41 average model derived from the MD trajectory (20,000–50,000 ps). The RMSD of structures of the trajectory versus the starting model (left) and the evolution of the secondary structure elements (right) are reported in the inset.