Oligomerization of Huntingtin N-Terminal Fragment on a Phospholipid Bilayer Revealed by Molecular Dynamics Simulations

Abstract

The Huntingtin protein is characterized by a consecutive segment of glutamines that leads, when the number of repeats exceeds a certain length, to fibrillation. Misfolding of this amyloid protein is related to the Huntington's disease through pathways that could involve interactions with phospholipid membranes. For instance, the N-terminal region of Huntingtin (httNT) positioned just before the polyglutamine segment (QN) modulates its localization to the membrane-containing organelles of the cell and can, similarly to what is observed in other amyloid proteins, perturb the physical integrity of phospholipid bilayers. To date, however, the dynamics and equilibrium structures of httNT oligomers on membranes as well as the influence of the QN region on these remain poorly understood.With the help of all-atom explicit solvent molecular dynamics simulations, we observe that the httNTQN monomer insertion in phospholipid bilayers occurs through four main steps and significantly increases the stability of the alpha-helix conformation compared to in solution. We also observe that the QN region provides, through electrostatic interactions with the phospholipids' head group, a stable scaffold to ease the insertion of httNT's non-polar residues. While the httNT monomer conformation suggested from our simulations is in agreement with a recent NMR model, its orientation in the bilayer deviates by a few degrees, a difference that might be due to the formation of dimers during the experiment. Indeed, our simulations on the dynamics of httNT dimerization, which occurs through electrostatic interactions, suggest that it affects the peptides' orientation depending on the dimer topology. Overall, these results reveal key features, at the atomic level, of httNTQN monomer and dimer interactions with phospholipid bilayer complementing previous experimental observations.