Are long-range structural correlations behind the aggregration phenomena of polyglutamine diseases?

We have characterized the conformational ensembles of polyglutamine Qn peptides of various lengths n (ranging from 6 to 40), both with and without the presence of a C-terminal polyproline hexapeptide. For this, we used state-of-the-art molecular dynamics simulations combined with a novel statistical analysis to characterize the various properties of the backbone dihedral angles and secondary structural motifs of the glutamine residues. For Q40 (i.e., just above the pathological length ≃36 for Huntington's disease), the equilibrium conformations of the monomer consist primarily of disordered, compact structures with non-negligible α-helical and turn content. We also observed a relatively small population of extended structures suitable for forming aggregates including β- and α-strands, and β- and α-hairpins. Most importantly, for Q40 we find that there exists a long-range correlation (ranging for at least 20 residues) among the backbone dihedral angles of the Q residues. For polyglutamine peptides below the pathological length, the population of the extended strands and hairpins is considerably smaller, and the correlations are short-range (at most 5 residues apart). Adding a C-terminal hexaproline to Q40 suppresses both the population of these rare motifs and the long-range correlation of the dihedral angles. We argue that the long-range correlation of the polyglutamine homopeptide, along with the presence of these rare motifs, could be responsible for its aggregation phenomena.