Are Long-Range Structural Correlations Behind the Aggregration Phenomena of Polyglutamine Diseases?

We have characterized the conformational ensembles of polyglutamine [Image: see text] peptides of various lengths [Image: see text] (ranging from [Image: see text] to [Image: see text]), 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 [Image: see text] (i.e., just above the pathological length [Image: see text] for Huntington's disease), the equilibrium conformations of the monomer consist primarily of disordered, compact structures with non-negligible [Image: see text]-helical and turn content. We also observed a relatively small population of extended structures suitable for forming aggregates including [Image: see text]- and [Image: see text]-strands, and [Image: see text]- and [Image: see text]-hairpins. Most importantly, for [Image: see text] we find that there exists a long-range correlation (ranging for at least [Image: see text] 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 [Image: see text] residues apart). Adding a C-terminal hexaproline to [Image: see text] 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.