Polyglutamine Solution-State Structural Propensity Is Repeat Length Dependent.

Abstract

Expanded polyglutamine (polyQ) tracts in proteins, which are known to induce their aggregation, are associated with numerous neurodegenerative diseases. Longer polyQ tracts correlate with faster protein aggregation kinetics and a decreased age of onset for polyQ disease symptoms. Here, we use UV resonance Raman spectroscopy, circular dichroism spectroscopy, and metadynamics simulations to investigate the solution-state structures of the D2Q15K2 (Q15) and D2Q20K2 (Q20) peptides. Using metadynamics, we explore the conformational energy landscapes of Q15 and Q20 and investigate the relative energies and activation barriers between these low-energy structures. We compare the solution-state structures of D2Q10K2 (Q10), Q15, and Q20 to determine the dependence of polyQ structure on the Q tract length. We show that these peptides can adopt two distinct monomeric conformations: an aggregation-resistant PPII-like conformation and an aggregation-prone β-strand-like conformation. We find that longer polyQ peptides have an increased preference for the aggregation-prone β-strand-like conformation. This preference may play an important role in the increased aggregation rate of longer polyQ peptides that is thought to lead to decreased neurodegenerative disease age of onset for polyQ disease patients.