A simple lattice model that captures protein folding, aggregation and amyloid formation

Area of Science:

• Biophysics
• Computational Biology
• Protein Science

Background:

• Protein misfolding into amyloid fibrils is linked to neurodegenerative diseases like Alzheimer's and Parkinson's.
• Understanding factors driving protein fibril formation is crucial for disease research.
• Fully atomistic models are computationally limited for simulating long-timescale fibril formation.

Purpose of the Study:

• To develop a computationally feasible coarse-grained lattice model for studying protein folding and amyloid formation.
• To investigate the interplay between protein folding, amorphous aggregation, and fibril formation.
• To explore the role of amino acid sequence and hydrogen bonding in beta sheet and amyloid formation.

Main Methods:

• Developed a novel lattice model incorporating hydrogen bonds and side-chain directionality.
• Simulated protein folding, amorphous aggregation, and spontaneous fibril formation.
• Analyzed the influence of amino acid sequence on structural stability and fibril propensity.

Main Results:

• The model successfully simulates protein folding into beta-sheet-like structures.
• Spontaneous formation of cross-beta amyloid fibrils from short hydrophobic peptide sequences was observed.
• Both folded structures and fibrils formation are highly dependent on the amino acid sequence, especially hydrophobic content.

Conclusions:

• Hydrogen bonds alone are insufficient to initiate beta sheet formation; sequence-dependent interactions are critical.
• Hydrophobic sequences are more prone to forming beta sheets and amyloid structures.
• This model provides a platform for systematic investigation of factors governing amyloid formation.