 Are Long-Range Structural Correlations Behind the Aggregration Phenomena of Polyglutamine Diseases?Mahmoud Moradi, Volodymyr Babin, Christopher Roland and Celeste Sagui PLOS Computational Biology, 2012, vol. 8, issue 4, 1-1 Abstract: We have characterized the conformational ensembles of polyglutamine peptides of various lengths (ranging from to ), 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 (i.e., just above the pathological length for Huntington's disease), the equilibrium conformations of the monomer consist primarily of disordered, compact structures with non-negligible -helical and turn content. We also observed a relatively small population of extended structures suitable for forming aggregates including - and -strands, and - and -hairpins. Most importantly, for we find that there exists a long-range correlation (ranging for at least 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 residues apart). Adding a C-terminal hexaproline to 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. Author Summary: Nine neurodegenerative diseases are caused by polyglutamine (polyQ) expansions greater than a given threshold in proteins with little or no homology except for the polyQ regions. The diseases all share a common feature: the formation of polyQ aggregates and eventual neuronal death. Using molecular dynamics simulations, we have explored the conformations of polyQ peptides. Results indicate that for peptides (i.e., just above the pathological length for Hungtington's disease), the equilibrium conformations were found to consist primarily of disordered, compact structures with a non-negligible -helical and turn content. We also observed a small population of extended structures suitable for forming aggregates. For peptides below the pathological length, the population of these structures was found to be considerably lower. For longer peptides, we found evidence for long-range correlations among the dihedral angles. This correlation turns out to be short-range for the smaller polyQ peptides, and is suppressed (along with the extended structural motifs) when a C-terminal polyproline tail is added to the peptides. We believe that the existence of these long-range correlations in above-threshold polyQ peptides, along with the presence of rare motifs, could be responsible for the experimentally observed aggregation phenomena associated with polyQ diseases. Date: 2012 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1002501 DOI: 10.1371/journal.pcbi.1002501 Access Statistics for this article More articles in PLOS Computational Biology from Public Library of Science |
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