Abstract
Protein misfolding and aggregation is a pathogenic feature shared among at least ten polyglutamine (polyQ) neurodegenerative diseases. While solvent-solution interaction is a key factor driving protein folding and aggregation, the solvation properties of expanded polyQ tracts are not well understood. By using GPU-enabled all-atom molecular dynamics simulations of polyQ monomers in an explicit solvent environment, this study shows that solvent-polyQ interaction propensity decreases as the lengths of polyQ tract increases. This study finds a predominance in long-distance interactions between residues far apart in polyQ sequences with longer polyQ segments, that leads to significant conformational differences. This study also indicates that large loops, comprised of parallel β-structures, appear in long polyQ tracts and present new aggregation building blocks with aggregation driven by long-distance intra-polyQ interactions. Finally, consistent with previous observations using coarse-grain simulations, this study demonstrates that there is a gain in the aggregation propensity with increased polyQ length, and that this gain is correlated with decreasing ability of solvent-polyQ interaction. These results suggest the modulation of solvent-polyQ interactions as a possible therapeutic strategy for treating polyQ diseases.
Highlights
The polyglutamine diseases are caused by unstable expansions of CAG repeats resulting in proteins with expanded polyQ tracts
While polyQ protein folding, stability, and aggregation have been well described for the polyQ diseases [15, 16], the molecular mechanisms leading to protein misfolding and aggregation, at the atomic level, are not well understood
Consistent with the fact that the expansion of polyQ sequence beyond a certain threshold, specific for each polyQ disease, triggers pathogenesis [50], numerous observations have suggested that the polyQ tract by itself may play a central role in the pathogenesis of the ten known polyQ neurodegenerative diseases [13]
Summary
The polyglutamine (polyQ) diseases are caused by unstable expansions of CAG repeats resulting in proteins with expanded polyQ tracts. The polyQ diseases include Huntington’s disease (HD), the spinocerebellar ataxias (SCAs 1, 2, 3, 6, 8, 7, 17), dentatorubral-pallidoluysian atrophy (DRPLA), and spinal and bulbar muscular atrophy (SBMA) [1,2,3,4,5,6]. Pathogenesis in these diseases is associated with abnormal polyQ protein folding [7,8,9] and resultant neuronal inclusion body formation [8, 10,11,12,13,14]. While polyQ protein folding, stability, and aggregation have been well described for the polyQ diseases [15, 16], the molecular mechanisms leading to protein misfolding and aggregation, at the atomic level, are not well understood.
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