There is a strong negative correlation between the
polyglutamine (
polyQ) domain length (Q-length) in the intrinsically disordered
Huntingtin protein (Htt) exon-1 and the age of onset of
Huntington's disease (HD).
PolyQ of Q-length longer than 40 has the propensity of forming very compact aggregate structures, leading to HD at full penetrance. Recent advances in nanobiotechnology provided a new platform for the development of novel diagnosis and
therapeutics. Here, we explore the possibility of utilizing 2D-nanomaterials to inhibit the formation of supercompact
polyQ structures through the so-called "folding-upon-binding" where the
protein structure is dependent on the binding substrate. Using molecular dynamics simulations, we characterize two
polyQ peptides with Q-length of 22 (Q22, normal length) and 46 (Q46, typical length causing HD) binding to both
graphene and
molybdenum disulfide (MoS2) nanosheets, which have been applied as antibacterial or
anticancer agents. Upon binding, Q22 unfolds and elongates on both grapheme and MoS2 surfaces, regardless of its initial conformation, with
graphene showing slightly stronger effect. In contrast, initially collapsed Q46 remains mostly collapsed within our simulation time on both nanosheets even though they do provide some "stretching" to Q46 as well. Further analyses indicate that the hydrophobic nature of
graphene/MoS2 promotes the stretching of
polyQ on nanosheets. However, there is strong competition with the intra-
polyQ interactions (mainly internal hydrogen bonds) leading to the disparate folding/binding behaviors of Q22 and Q46. Our results present distinct Q-length specific behavior of the
polyQ domain upon binding to two types of 2D-nanomaterials which holds clinical relevance for
Huntington's disease.