The β-sheet breakers and π-stacking

Area of Science:

• Neuroscience
• Biochemistry
• Computational Biology

Background:

• Amyloid-beta (Aβ) fibrillation is central to Alzheimer's disease pathogenesis.
• Beta-sheet breakers are peptides that inhibit Aβ fibrillation and dissolve existing fibrils.
• The precise mechanism of β-sheet breaker inhibition remains unclear.

Purpose of the Study:

• To investigate the role of consecutive phenylalanine (Phe) residues in β-sheet breaker peptides.
• To elucidate the mechanism of amyloidogenesis inhibition by β-sheet breakers using molecular dynamics simulations.

Main Methods:

• Performed 30-ns molecular dynamics (MD) simulations on two β-sheet breakers: iAβ5 (LPFFD) and iAβ6 (LPFFFD).
• Analyzed peptide conformations, focusing on the stacking of Phe residues.
• Calculated electrostatic free energy contributions for different conformers.

Main Results:

• Identified a tendency for Phe rings within the peptides to form stacked conformations.
• Observed significantly lower electrostatic free energy for a specific three-ring stacked conformer (c2) of iAβ6 compared to other conformers.
• This suggests favorable interactions of the c2 conformer with amyloid fibrils.

Conclusions:

• Hypothesize that inhibition involves π-stacked Phe residues in β-sheet breakers competing with π-stacking in Aβ fibrils.
• iAβ6, with its propensity for stable Phe-ring stacking, is a promising candidate for developing amyloidogenesis inhibitors.