Markov State Models Reveal How hLL-37_17-29 Tetramers Relax from a Disordered State to a Cross-α Amyloid Geometry.

Area of Science:

• Biomaterials Science
• Structural Biology
• Computational Chemistry

Background:

• Cross-α amyloids are functional peptide assemblies crucial for bacterial biofilm formation and antibiotic resistance.
• Synthetic cross-α architectures offer rigidity and piezoelectric properties, making them promising for biomaterial applications.
• The antimicrobial peptide hLL-37_17-29 forms cross-α amyloid structures, but the organization pathway from disordered aggregates to ordered arrangements is unclear.

Purpose of the Study:

• To elucidate the relaxation pathways and kinetic landscape governing the formation of cross-α amyloid structures in hLL-37_17-29 tetramers.
• To understand the molecular mechanisms driving the spontaneous emergence of ordered cross-α geometry from disordered peptide bundles in solution.

Main Methods:

• Construction of Markov state models (MSMs) utilizing 50 μs of molecular dynamics simulations.
• Employing detailed structural descriptors to analyze the relaxation landscape of hLL-37_17-29 tetramers.
• Characterization of the dominant metastable state and its structural and dynamic properties.

Main Results:

• A dominant metastable state was identified, accurately reproducing the crystallographic cross-α geometry and demonstrating the emergence of order from disorder.
• The cross-α arrangement was observed to form spontaneously in solution, a phenomenon previously seen only in solid-state studies.
• The relaxation process is driven by hydrophobic core consolidation and exhibits a self-healing mechanism for aggregate stability.

Conclusions:

• This study provides the first detailed kinetic and structural characterization of cross-α amyloid relaxation in hLL-37_17-29.
• Insights into the self-organization and self-healing mechanisms of cross-α amyloids advance molecular understanding.
• Findings offer design principles for creating stable, self-organizing peptide-based biomaterials.