Clustering and Fibril Formation during GNNQQNY Aggregation: A Molecular Dynamics Study.

Area of Science:

• Biophysics
• Molecular Biology
• Protein Aggregation

Background:

• The precise kinetic pathways of peptide clustering and fibril formation remain unclear.
• Understanding these pathways is crucial for deciphering protein misfolding diseases.

Purpose of the Study:

• To investigate the initial clustering kinetics and transient morphologies during the aggregation of the GNNQQNY heptapeptide fragment from yeast prion protein Sup35.
• To elucidate the molecular events leading to stable fibril-like structures.

Main Methods:

• Utilized a mid-resolution coarse-grained molecular dynamics model (Bereau and Deserno).
• Simulated aggregation pathways from free monomers to large clusters, increasing system size to 72 peptides.
• Developed a novel cluster helicity parameter to quantify fibril-like structures.

Main Results:

• Identified a cooperative process for fibril-like structure formation, requiring a critical cluster size (M⋆≈25 monomers).
• Determined that the terminal tyrosine residue is a key structural determinant for helical fibril formation.
• Observed that growing aggregates undergo internal reorganization into more compact structures.

Conclusions:

• The study supports and quantifies a two-step aggregation model: initial amorphous cluster formation followed by rearrangement into mature, twisted structures.
• Demonstrated that fibril formation is a size-dependent, cooperative process.
• Highlighted the critical role of specific residues (terminal tyrosine) in dictating fibril morphology.