Structural Properties of Polyglutamine Aggregates Investigated via Molecular Dynamics Simulations

Abstract

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 on 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.

Molecular dynamics study of dipalmitoylphosphatidylcholine lipid layer self-assembly onto a single-walled carbon nanotube

“…The time step size was 2 fs. Based on previous work, the SWNT atoms were modeled as uncharged Lennard-Jones particles using sp 2 carbon parameters [23,24] with a cross section of CC = 0.365 nm, and a depth of the potential well of CC = 0.465 kJ/mol. For the DPPC molecule, we used Berger's parameters [25].…”

Molecular Mechanism of Huntington’s Disease — A Computational Perspective

“…CE was investigated on other polypeptides (Tsemekhman et al 2007;Varga & Kovács 2005;Horvath et al 2004Horvath et al , 2005Improta & Barone 2004;Zhao & Wu 2002;Wieczorek & Dannenberg 2003;Viswanathan et al 2004;Scheiner & Kar 2005) with the application of first principle methods. However, here we provide a summary of the first study in which the presence and the importance of CE in the H-bonds of Qs side chains was verified with DFT approaches (Rossetti et al 2008). We performed first principles DFT-PBE (Benedek et al 2005;Morozov et al 2004;Perdew et al 1996) calculations on polyQ peptides of increasing complexity, assembled in parallel h β-sheets (Tsemekhman et al 2007;Koch et al 2005;Beke et al 2006;Perczel et al 2005).…”

“…Among these, several studies investigated the dependence of the structural stability of the circular β-helix, as well as of other possible structures, on the Q length (Stork et al 2005;Merlino et al 2006;Ogawa et al 2008;Rossetti et al 2008;Hajime et al 2008;Khare et al 2005), leading sometimes to conflicting views. For example classical MD studies showed that β-helices with three turns were unstable with circular geometries, being, instead, stable in a triangular β-helix shape.…”

“…Furthermore, it was suggested that the toxicity of mut-Htt may be simply due to the fact that polyQ tracts are inherently toxic sequences, whose deleterious effects gradually increase with their length (Klein et al 2007). We investigated the influence of the polyQ length on the structural stability of monomers and oligomers by performing atomistic MD simulations on different β-helical models featuring a number of Qs below and well beyond the disease threshold (Rossetti et al 2008). We considered the circular (Raetz & Roderick 1995) and triangular β-helices (Stork et al 2005;Perutz et al 2002) as shapes of the oligomers, since these are the only models consistent with the 'structural threshold hypothesis'.…”

“…Although circular β-helix is only one of the possible polyQ structures (Sikorski & Atkins 2005;Zanuy et al 2006), we investigated it since we demonstrated by classical MD studies that the structural stability of the polyQ oligomers was independent from the β-sheet shape (Rossetti et al 2008). In this study, in fact, we aimed at providing a qualitative description of CE.…”