Structural Properties of Polyglutamine Aggregates Investigated via Molecular Dynamics Simulations

Polyglutamine (polyQ) beta-stranded aggregates constitute the hallmark of Huntington disease. The disease is fully penetrant when Q residues are more than 36-40 ("disease threshold"). Here, based on a molecular dynamics study on polyQ helical structures of different shapes and oligomeric states, we suggest that the stability of the aggregates increases with the number of monomers, while it is rather insensitive to the number of Qs in each monomer. However, the stability of the single monomer does depend on the number of side-chain intramolecular H-bonds, and therefore oil the number of Qs. If such number is lower than that of the disease threshold, the beta-stranded monomers are unstable and hence may aggregate with lower probability, consistently with experimental findings. Our results provide a possible interpretation of the apparent polyQ length dependent-toxicity, and they do not support the so-called "structural threshold hypothesis", which supposes a transition from random coil to a beta-sheet structure only above the disease threshold

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

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

Polyglutamine Induced Misfolding of Huntingtin Exon1 is Modulated by the Flanking Sequences

Polyglutamine (polyQ) expansion in exon1 (XN1) of the huntingtin protein is linked to Huntington's disease. When the number of glutamines exceeds a threshold of approximately 36–40 repeats, XN1 can readily form amyloid aggregates similar to those associated with disease. Many experiments suggest that misfolding of monomeric XN1 plays an important role in the length-dependent aggregation. Elucidating the misfolding of a XN1 monomer can help determine the molecular mechanism of XN1 aggregation and potentially help develop strategies to inhibit XN1 aggregation. The flanking sequences surrounding the polyQ region can play a critical role in determining the structural rearrangement and aggregation mechanism of XN1. Few experiments have studied XN1 in its entirety, with all flanking regions. To obtain structural insights into the misfolding of XN1 toward amyloid aggregation, we perform molecular dynamics simulations on monomeric XN1 with full flanking regions, a variant missing the polyproline regions, which are hypothesized to prevent aggregation, and an isolated polyQ peptide (Qn). For each of these three constructs, we study glutamine repeat lengths of 23, 36, 40 and 47. We find that polyQ peptides have a positive correlation between their probability to form a β-rich misfolded state and their expansion length. We also find that the flanking regions of XN1 affect its probability to^x_page_count=28 form a β-rich state compared to the isolated polyQ. Particularly, the polyproline regions form polyproline type II helices and decrease the probability of the polyQ region to form a β-rich state. Additionally, by lengthening polyQ, the first N-terminal 17 residues are more likely to adopt a β-sheet conformation rather than an α-helix conformation. Therefore, our molecular dynamics study provides a structural insight of XN1 misfolding and elucidates the possible role of the flanking sequences in XN1 aggregation

Mata do usuwania zanieczyszczeń ropopochodnych

The aim of the investigation was to design and prepare a fibrous mat containing chicken feathers as an active filling to absorb spills of petroleum derivatives. The fibrous mat used to remove petroleum contamination consists of an active layer from chicken feathers (the main waste from poultry plants), placed between two layers of hydrophobic material of PP or PES in the form of nonwovens. The mata designed are characterised by excellent sorption of a wide range of hydrophobic petroleum substances, selectivity (sorption of liquid immiscible with water) and subdivision even at the highest saturation of the mat. Oil binder mats based on chicken feathers have been found to be highly effective in absorbing spilled oil from water surface. The material can be used, directly on a water surface regardless of weather conditions, as well as on other surfaces such as concrete or asphalt to fight leakages of oily substances. The mats are light, easy to store and use, and inexpensive. Apart from sorptive proprieties of the mats designed, the possibility of biological utilisation of petroleum contamination by means of a bioremediation method was introduced in the article.Celem badań było otrzymanie maty włóknistej do usuwania wycieków substancji ropopochodnych Mata włóknista do usuwania ropopochodnych zanieczyszczeń składającej się z warstwy aktywnej zbudowanej z rozdrobnionych piór drobiowych, umieszczonej między dwiema warstwami hydrofobowego materiału z PP, lub PES w postaci włókniny, dzianiny lub siatki. Mata taka charakteryzuje się doskonałą sorpcją substancji ropopochodnych, selektywnością (sorpcja cieczy niemieszających się z wodą) oraz niezatapialnością nawet w stanie najwyższego nasycenia maty. Pióra drobiowe zastosowane jako pochłaniacz ropy okazały się bardzo skuteczne w usuwaniu zanieczyszczeń olejowych z powierzchni wody. Oprócz właściwości sorpcyjnych, w artykule przedstawiono możliwości biologicznej utylizacji zanieczyszczeń ropopochodnych osadzonych na piórach