Abstract
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.
Highlights
Neurodegenerative Huntington’s disease (HD) is caused by expansion of the trinucleotide CAG repeats in exon-1 of the HD gene, the mutation that encodes an extended polyglutamine tract within the N-terminal exon-1 of the Huntingtin protein (Htt) (Macdonald et al, 1993)
Expanded polyQ regions form oligomers that aggregate into large, insoluble protein complexes, which may subsequently mature to observable fibrils (Perutz et al, 1994)
To investigate the influence of graphene and MoS2 nanosheets on the polyQ structure, we calculated the radius of gyration (Rg) and root-mean-square deviation (RMSD) of Q22 and Q46 as a function of time (Figure 2)
Summary
Neurodegenerative Huntington’s disease (HD) is caused by expansion of the trinucleotide CAG repeats in exon-1 of the HD gene, the mutation that encodes an extended polyglutamine (polyQ) tract within the N-terminal exon-1 of the Huntingtin protein (Htt) (Macdonald et al, 1993). Expanded polyQ regions form oligomers that aggregate into large, insoluble protein complexes, which may subsequently mature to observable fibrils (Perutz et al, 1994). PolyQ length and structure are critical for posited neurotoxicity mechanisms caused by oligomers and larger aggregates (Miller et al, 2011). The increased compactness at long Q-lengths indicates that the polyQ domain may result in increased neural toxicity by inducing distinct morphological changes throughout the entire Htt exon-1 protein (Kang et al, 2017)
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