Probing the Conformational Preference to β-Strand during Peptide Self-Assembly

Area of Science:

• Biophysics
• Materials Science
• Computational Chemistry

Background:

• Alanine-rich tetrapeptides, such as A3K, predominantly adopt polyproline II helices in dilute solutions.
• Peptide self-assembly into ordered structures, like amyloid fibrils, often involves conformational changes.

Purpose of the Study:

• To investigate the conformational transitions of alanine-rich tetrapeptides during self-assembly.
• To understand the energetic landscape governing peptide self-assembly and fibril formation.

Main Methods:

• Free energy calculations in implicit solvent to screen peptide conformations.
• Umbrella sampling simulations in explicit solvent to validate findings and study dynamic processes.
• Analysis of interpeptide distances and comparison with experimental data (X-ray diffraction).

Main Results:

• Only beta-strand conformations allow for close packing necessary for self-assembly.
• Implicit solvent calculations accurately predict free energy minima corresponding to self-assembly.
• A significant energy barrier exists due to water molecule interactions, suggesting initial assembly in polyproline II before transitioning to beta-strands.

Conclusions:

• Peptide self-assembly involves a dynamic conformational transition from polyproline II to beta-strands.
• Implicit solvent methods are effective for rapid screening of favorable peptide configurations.
• The findings support a 'dock and lock' mechanism for amyloid fibril growth.