54 / 89
50
Biophysics of Proteins at Surfaces: Assembly, Activation, Signaling
Poster Abstracts
4-POS
Board 4
Probing the Anchoring of the Huntingtin N-Terminal on a Phospholipid Bilayer Using All-
Atom Simulations
Vincent Binette
, Sébastien Côté, Normand Mousseau.
Université de Montréal, Montreal, Canada.
Huntington's disease is characterized by motor dysfunctionalities and the loss of cognitive
function and associated with the aggregation of the huntingtin protein into amyloid fibrils. The
exon1 of huntingtin is crucial because it is sufficient to reproduce the phenotypes and
aggregation features of the Huntington disease. It is composed of a 17 amino acids sequence
(Htt17) at its N-terminal, a polyglutamine repeat (Q
N
) domain and a proline rich domain (C38).
Huntingtin’s aggregation is triggered when its Q
N
domain surpasses the threshold of 36
glutamines. Htt17 is particularly important because of its potential role as a membrane anchor
that could accelerate the fibrillation process. Recent solution and solid-state NMR experiments
have unveiled the structure and the orientation of Htt17 in DPC micelles and POPC bilayer [1].
Here, we use all-atom explicit solvent molecular dynamics (MD) and Hamiltonian replica
exchange (HREX) simulations to refine the experimental picture focusing, in particular, on the
characterization of the dynamic and thermodynamic of the proposed NMR model inside a
phospholipid bilayer. We find that the fully formed α-helix is more stable in the membrane than
the proposed NMR model in micelles and that Htt17’s hydrophobic plane is almost parallel to
the membrane. In this position, key nonpolar residues are deeply inserted and hidden from the
solvent. Simulations also reveal localized membrane perturbation around Htt17 due to the
extension of neighbor phospholipid acyl chains to cover the nonpolar surface of Htt17. These
types of membrane deformations were shown to promote dimerization. Htt17 dimerization could
therefore be initiated by electrostatic interactions as the charged residues stay mostly accessible
to the solvent. Htt17 dimers could form large aggregates that radically change the membrane
properties and permeation.
1. Michalek, M. et al., Biochemistry, (2013)