Assessing polyglutamine conformation in the nucleating event by molecular dynamics simulations

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Biology

Background:

• Polyglutamine (polyQ) diseases are inherited disorders.
• Pathology is caused by expanded polyQ stretches forming β-sheets.
• Amyloidogenesis involves a difficult-to-detect nucleus.

Purpose of the Study:

• To assess the conformation of the polyQ stretch in the nucleus initiating fibrillization.
• To compare the kinetic stability of different polyQ structures.

Main Methods:

• Atomistic molecular dynamics simulations in explicit solvent.
• Analysis of polyQ peptide conformations (Q40) in the pathological range.

Main Results:

• Steric zipper and nanotube-like structures are not kinetically stable for initiating fibrillization.
• β-hairpin-based (β-sheet, β-sheetstack) and α-helical conformations are kinetically stable.
• Different initiating structures may explain polyQ aggregate polymorphism.

Conclusions:

• The study identifies kinetically stable conformations for polyQ fibrillization initiation.
• Findings offer insights into the structural basis of polyQ aggregate diversity.
• This work advances understanding of polyglutamine disease mechanisms.