Alterations To The Conformational Ensemble And Intermolecular Associations Of Polyglutamine Due To Charged Side Chains At The N- And C-Termini

Expanded polyglutamine (polyQ) tracts are associated with several neurodegenerative disorders including Huntington's disease (HD). Biophysical and computational characterization of polyQ peptides has been used to probe the intrinsic properties of polyQ and to study the mechanism by which polyQ aggregates. Experiments with the peptide construct K2QNK2 show a pronounced lag phase. This has led to the proposal that polyQ peptides aggregate via a homogeneous nucleation mechanism. Most in vitro kinetics experiments with polyQ have been performed with terminal lysine residues to enhance solubility. It has been assumed that these charged residues do not affect the properties of the polyQ peptide or the mechanism of aggregation. Recent simulations and experiments call this assumption into question. We present results from computational studies on the effects of charged side chains at the N- and C-termini to understand how the intrinsic length dependent properties and intermolecular interactions of polyQ constructs are altered by terminal charges. This study is based on simulations utilizing the ABSINTH solvation model. The results show that below a certain length scale, the conformational ensemble of polyQ is altered by finite size and charge effects and the intrinsic polymeric behavior of polyQ is recovered at high molecular weights. These results make the point that simple polymeric models, such as the worm-like-chain model, fail to capture these trends and their application to polyQ systems is dubious. PolyQ intermolecular interactions are altered by long-range electrostatics and this persists over a large length scale. Lastly, we show that the charged terminal residues alter the amplitudes of intra-polyQ conformational fluctuations. Since these fluctuations are involved in modulating aggregation, this yields insight into how polyQ flanking sequences play a role in the mechanism of polyQ aggregation.