Hydrogen Bonding Cooperativity in polyQ β-Sheets from First Principle Calculations

Area of Science:

• Biochemistry
• Computational Chemistry
• Neuroscience

Background:

• Polyglutamine (PQ) β-sheet aggregates are implicated in Huntington's disease (HD) pathogenesis.
• The role of hydrogen bond (H-bond) network cooperativity in PQ aggregate structure and energetics is poorly understood.
• Direct quantification of H-bond cooperativity in PQ aggregates is lacking.

Purpose of the Study:

• To investigate and quantify the effect of H-bond network cooperativity in polyglutamine β-sheet aggregates.
• To elucidate the structural and energetic contributions of glutamine side chains to aggregate stability.
• To understand the unique properties of polyglutamine aggregation in the context of neurodegenerative diseases like HD.

Main Methods:

• Density Functional Theory (DFT) simulations.
• Hybrid DFT/Molecular Mechanics (MM) simulations.
• Simulations performed on polyglutamine β-sheet structures in both vacuum and aqueous solution.

Main Results:

• Observed cooperative effects of glutamine side chains in both perpendicular and parallel directions relative to the polyglutamine backbone.
• Demonstrated that this cooperative behavior provides significant extra-stabilization to the β-sheet structures.
• Identified a unique stabilization mechanism not typically observed in standard β-sheets.

Conclusions:

• Glutamine side chain cooperativity plays a crucial role in the structural integrity and energetics of polyglutamine aggregates.
• This cooperative stabilization mechanism contributes to the unique aggregation properties of polyglutamines.
• Findings offer insights into the molecular basis of Huntington's disease and potential therapeutic targets.