Side Chain Geometry Determines the Fibrillation Propensity of a Minimal Two-Beads-per-Residue Peptide Model

Area of Science:

• Biophysics
• Computational Chemistry
• Molecular Biology

Background:

• Peptide aggregation and fibrillation are critical to understanding diseases like Alzheimer's.
• Previous models identified interchain attraction and bending stiffness as key factors but did not achieve fibrillation.
• A simplified implicit solvent peptide model was insufficient for simulating fibril formation.

Purpose of the Study:

• To investigate the molecular origins of fibril formation in peptides.
• To develop a minimal bead-based model capable of simulating fibrillation.
• To elucidate the role of side chain geometry and terminal modifications in fibrillation propensity.

Main Methods:

• Utilized a two-beads-per-residue model, distinguishing backbone and side chain atoms.
• Incorporated modified terminal beads to study capping effects.
• Simulated peptide aggregation without assuming secondary structure.

Main Results:

• Demonstrated that side chain geometry is a primary determinant of fibrillation propensity.
• Showed that modified terminal beads modulate the fibrillation tendency.
• Developed the simplest bead-based model to date that successfully simulates fibrillation.

Conclusions:

• Side chain geometry and terminal capping are crucial factors in peptide fibril formation.
• The developed two-beads-per-residue model offers a simplified yet effective approach to studying fibrillation.
• This work provides fundamental insights into the molecular mechanisms underlying peptide aggregation and fibrillation.