title: Are long-range structural correlations behind the aggregration phenomena of polyglutamine diseases?
abstract: 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.
authors.affiliation: Center for High Performance Simulations (CHiPS) and Department of Physics, North Carolina State University, Raleigh, North Carolina, USA.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Moradi
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Babin
authors.forename: Christopher
authors.initials: C
authors.lastname: Roland
authors.forename: Celeste
authors.initials: C
authors.lastname: Sagui
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003198:Computer Simulation; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D013223:Statistics as Topic
chemical_list: D010455:Peptides; C097188:polyglutamine