Structural determinants of polyglutamine protofibrils and crystallites

Area of Science:

• Molecular Biology
• Biophysics
• Computational Biology

Background:

• Nine inherited neurodegenerative diseases are linked to CAG codon expansion.
• Expanded polyglutamine tracts (> ~36 residues) form intraneuronal protein aggregates, often cross-β amyloid fibrils.

Purpose of the Study:

• To probe structural stability and dynamics of polyglutamine aggregate models using molecular dynamics simulations.
• To test the stability of parallel and antiparallel β sheets and analyze side-chain interactions.

Main Methods:

• Fully atomistic molecular dynamics simulations.
• Analysis of β sheet stability, steric interfaces, and side-chain dipole alignments.
• Construction and stability testing of Q40 monomeric models.

Main Results:

• Simulations reconciled experimental data, showing initial oligomers forming stable crystals on microsecond timescales.
• Previously stable models proved unstable, while unstable models became stable with corrected symmetry and side-chain packing.
• Stable monomers were identified and tested for aggregation thresholds.

Conclusions:

• The study explains and resolves discrepancies in polyglutamine aggregate structures.
• Tightly packed side chains and hydrogen bonds stabilize the aggregates.
• Results support the concept of an aggregation threshold for polyglutamine diseases.