Assessing Polyglutamine Conformation in the Nucleating Event by Molecular Dynamics Simulations

Polyglutamine (polyQ) diseases comprise a group of dominantly
inherited
pathology caused by an expansion of an unstable polyQ stretch which
is presumed to form β-sheets. Similar to other amyloid pathologies,
polyQ amyloidogenesis occurs via a nucleated polymerization mechanism,
and proceeds through energetically unfavorable nucleus whose existence
and structure are difficult to detect. Here, we use atomistic molecular
dynamics simulations in explicit solvent to assess the conformation
of the polyQ stretch in the nucleus that initiates polyQ fibrillization.
Comparison of the kinetic stability of various structures of polyQ
peptide with a Q-length in the pathological range (Q40)
revealed that steric zipper or nanotube-like structures (β-nanotube
or β-pseudohelix) are not kinetically stable enough to serve
as a template to initiate polyQ fibrillization as opposed to β-hairpin-based
(β-sheet and β-sheetstack) or α-helical conformations.
The selection of different structures of the polyQ stretch in the
aggregation-initiating event may provide an alternative explanation
for polyQ aggregate polymorphism.