Polyglutamine Solution-State Structural Propensity Is Repeat Length Dependent

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.