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

PLoS Computational Biology
Mahmoud MoradiCeleste Sagui

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 pop...Continue Reading

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Citations

Oct 30, 2012·Nucleic Acids Research·Mahmoud MoradiCeleste Sagui
Jul 16, 2014·Journal of Chemical Theory and Computation·Mahmoud Moradi, Emad Tajkhorshid
Jun 25, 2013·The Journal of Physical Chemistry Letters·Mahmoud Moradi, Emad Tajkhorshid
Jun 18, 2015·Journal of Chemical Theory and Computation·Mingjun YangAlexander D MacKerell
Feb 26, 2016·ACS Chemical Neuroscience·Yuan ZhangCeleste Sagui
Jan 22, 2015·ACS Chemical Neuroscience·Viet Hoang ManCeleste Sagui
Nov 27, 2014·Journal of Molecular Graphics & Modelling·Yuan Zhang, Celeste Sagui
May 23, 2017·The Journal of Physical Chemistry. B·David PunihaoleSanford A Asher
Jul 2, 2017·Scientific Reports·Mingjun YangAlexander D MacKerell

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Methods Mentioned

BETA
X-ray

Software Mentioned

STRIDE
AMBER
PolyP
DSSP
VMD

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