  Identifying the driving forces and the mechanism of association of
huntingtin-exon1, a close marker for the progress of Huntington's disease, is
an important prerequisite towards finding potential drug targets, and
ultimately a cure. We introduce here a modelling framework based on a key
analogy of the physico-chemical properties of the exon1 fragment to block
copolymers. We use a systematic mesoscale methodology, based on Dissipative
Particle Dynamics, which is capable of overcoming kinetic barriers, thus
capturing the dynamics of significantly larger systems over longer times than
considered before. Our results reveal that the relative hydrophobicity of the
poly-glutamine block as compared to the rest of the (proline-based) exon1
fragment, ignored to date, constitutes a major factor in the initiation of the
self-assembly process. We find that the assembly is governed by both the
concentration of exon1 and the length of the poly-glutamine stretch, with a low
length threshold for association even at the lowest volume fractions we
considered. Moreover, this self-association occurs irrespective of whether the
glutamine stretch is in random coil or hairpin configuration, leading to
spherical or cylindrical assemblies, respectively. We discuss the implications
of these results for reinterpretation of existing research within this context,
including that the routes towards aggregation of exon1 may be distinct to those
of the widely studied homopolymeric poly-glutamine peptides.
