Sequence dependent aggregation of peptides and fibril formation

Area of Science:

• Biophysics
• Computational Biology
• Protein Science

Background:

• Understanding protein misfolding diseases requires knowledge of how amino acid sequences influence protein aggregation.
• Amyloid fibril formation is a hallmark of many neurodegenerative diseases.

Purpose of the Study:

• To investigate the relationship between amino acid sequence and amyloid fibril formation using computational simulations.
• To explore how sequence characteristics affect the thermodynamics and structure of peptide aggregates.

Main Methods:

• Monte Carlo simulations were employed to model the aggregation of short peptides.
• A coarse-grained model incorporating hydrophobic-polar (HP) sequences and correlated side chain orientations was utilized.

Main Results:

• Significant heterogeneity in aggregate structures and aggregation thermodynamics was observed across different HP sequences.
• Fibril-like aggregates were identified for sequences containing the HPH pattern, while others formed helix bundles or disordered aggregates.
• Aggregation transition temperatures varied widely, indicating sequence-specific aggregation propensity at physiological temperatures.

Conclusions:

• Amino acid sequence plays a crucial role in selecting specific fibril-like aggregate structures.
• The presence of a structural template can influence fibril formation even in peptides with unrelated sequences.
• Fibril formation follows a nucleation and growth mechanism, and non-aggregation-prone peptides can be converted in the presence of aggregation-prone ones.