Structural transitions and oligomerization along polyalanine fibril formation pathways from computer simulations

Area of Science:

• Computational chemistry
• Biophysics
• Materials science

Background:

• Peptide aggregation is central to various biological processes and diseases.
• Understanding the kinetics and intermediate structures is crucial for controlling self-assembly.

Purpose of the Study:

• To investigate the aggregation kinetics and intermediate structures of a large peptide system.
• To elucidate the pathway leading to fibril formation using advanced simulation techniques.

Main Methods:

• Discontinuous molecular dynamics simulations.
• Utilized the intermediate-resolution protein model, PRIME.
• Simulated 192 polyalanine (KA(14) K) peptides at 5 mM and T* = 0.13.

Main Results:

• Tracked populations and transitions between monomers, amorphous aggregates, beta sheets, hybrid aggregates, and fibrils.
• Identified a pathway starting with amorphous aggregates, followed by rearrangement into beta sheets and hybrid structures.
• Fibril formation involves stacking of beta sheets and rearrangement of hybrid aggregates.

Conclusions:

• The rearrangement of amorphous aggregates into beta sheets is a critical, necessary step in fibril formation.
• The study provides detailed insights into the multi-step process of peptide self-assembly into ordered fibrillar structures.