Mapping Free-Energy Landscapes to Decipher Amphiphilic Peptide Multistep Self-Assembly

Area of Science:

• Biomaterials Science
• Chemical Physics
• Molecular Biology

Background:

• Peptide self-assembly forms crucial biological structures and advanced biomaterials.
• The thermodynamic driving forces behind complex, multistep self-assembly pathways are not fully understood.

Purpose of the Study:

• To elucidate the thermodynamic landscape of multistep peptide self-assembly.
• To investigate the role of liquid-liquid phase separation (LLPS) in peptide fibril formation.

Main Methods:

• Utilized temperature as a tunable parameter to map the free-energy landscape of peptide self-assembly.
• Analyzed the energetic contributions (enthalpy and entropy) of distinct assembly stages.

Main Results:

• Identified an initial enthalpy-driven, yet barrier-limited, LLPS clustering.
• Subsequent nucleation and fibril growth are governed by negative entropic barriers.
• LLPS was determined to be the rate-limiting step with the highest Gibbs free-energy barrier (+26 kJ mol-1).

Conclusions:

• Established a generalizable framework for understanding multistep biomolecular self-organization.
• Findings have implications for designing novel adaptive biomaterials.
• Provides insights into aberrant phase transitions linked to diseases.