Energy interactions in amyloid-like fibrils from NNQQNY

Area of Science:

• Biophysics
• Computational Chemistry
• Structural Biology

Background:

• Amyloid fibers are protein aggregates implicated in diseases.
• Experimental determination of interactions within amyloid fibers is challenging.
• The yeast prion-like protein Sup35 contains hexapeptide repeats (NNQQNY) that form amyloid.

Purpose of the Study:

• To computationally analyze the energetic interactions in amyloid fibers.
• To model the formation of amyloid fibrils at different organizational levels.
• To investigate the role of hydrogen bonds and aromatic interactions in fibril stability.

Main Methods:

• Large-scale MP2 (Møller–Plesset perturbation theory) calculations were employed.
• Dimers and trimers of the NNQQNY hexapeptide were used as model systems.
• Analysis of energy interactions at three organizational levels of fibril formation.

Main Results:

• Beta-sheet formation is the most energetic process, stabilized by hydrogen bonds and van der Waals interactions.
• Aromatic ring stacking, particularly of tyrosine residues, enhances aggregate stability.
• Steric zipper formation, the basic unit of proto-filaments, involves dispersion forces and hydrogen bonds.
• Interactions between beta-sheets via tyrosine rings are cooperative and driven by dispersion effects.

Conclusions:

• Hydrogen bonds and van der Waals forces are critical for beta-sheet formation in amyloid fibers.
• Aromatic interactions, especially tyrosine stacking, significantly contribute to amyloid aggregate stability.
• Computational analysis provides insights into amyloid structure and dynamics, correlating with experimental observations like solid-state NMR.