title: Atomistic mechanisms of huntingtin N-terminal fragment insertion on a phospholipid bilayer revealed by molecular dynamics simulations.
abstract: The huntingtin protein is characterized by a segment of consecutive glutamines (Q(N)) that is responsible for its fibrillation. As with other amyloid proteins, misfolding of huntingtin is related to Huntington's disease through pathways that can involve interactions with phospholipid membranes. Experimental results suggest that the N-terminal 17-amino-acid sequence (htt(NT)) positioned just before the Q(N) region is important for the binding of huntingtin to membranes. Through all-atom explicit solvent molecular dynamics simulations, we unveil the structure and dynamics of the htt(NT)Q(N) fragment on a phospholipid membrane at the atomic level. We observe that the insertion dynamics of this peptide can be described by four main steps-approach, reorganization, anchoring, and insertion-that are very diverse at the atomic level. On the membrane, the htt(NT) peptide forms a stable α-helix essentially parallel to the membrane with its nonpolar side-chains-mainly Leu-4, Leu-7, Phe-11 and Leu-14-positioned in the hydrophobic core of the membrane. Salt-bridges involving Glu-5, Glu-12, Lys-6, and Lys-15, as well as hydrogen bonds involving Thr-3 and Ser-13 with the phospholipids also stabilize the structure and orientation of the htt(NT) peptide. These observations do not significantly change upon adding the Q(N) region whose role is rather to provide, through its hydrogen bonds with the phospholipids' head group, a stable scaffold facilitating the partitioning of the htt(NT) region in the membrane. Moreover, by staying accessible to the solvent, the amyloidogenic Q(N) region could also play a key role for the oligomerization of htt(NT)Q(N) on phospholipid membranes.
authors.affiliation: Département de Physique and Groupe de recherche sur les protéines membranaires (GEPROM), Université de Montréal, Montréal (Québec), Canada.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Côté
authors.forename: Guanghong
authors.initials: G
authors.lastname: Wei
authors.forename: Normand
authors.initials: N
authors.lastname: Mousseau
mesh_terms: D005973:Glutamine / Q000737:chemistry; D006801:Humans; D000071058:Huntingtin Protein; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism; D008954:Models, Biological; D056004:Molecular Dynamics Simulation; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism; D010743:Phospholipids / Q000737:chemistry* / Q000378:metabolism
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D008051:Lipid Bilayers; D009419:Nerve Tissue Proteins; D010743:Phospholipids; D005973:Glutamine
keywords: Huntingtin protein; Huntington's disease; all-atom explicit solvent simulations; httNTQN monomer; peptide-membrane interactions