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

Le résumé fourni par la source

The formation of fibrous architectures via peptide self-assembly underpins numerous biological functions and biomaterial applications; however, the thermodynamic origins of multistep assembly pathways remain elusive. Here, we map the complete free-energy landscape governing the liquid-liquid phase separation (LLPS)-mediated self-assembly of an amphiphilic peptide by exploiting temperature as a tunable parameter. We discover an unexpected thermodynamic mechanism: the initial LLPS-like clustering is enthalpy-driven but limited by a positive enthalpic barrier (+121 kJ mol-1), arising from the endothermic disruption of intramolecular hydrogen bonds before interpeptide contacts can form. Subsequent nucleation and fibril growth are governed by negative entropic barriers (-56 and -39 kJ mol-1, respectively), reflecting the reorganization cost of partially ordered oligomers. The energy landscape identifies LLPS as the rate-limiting step with the highest Gibbs free-energy barrier (+26 kJ mol-1). Our findings establish a generalizable framework for decoding multistep biomolecular self-organization, with implications for designing adaptive biomaterials and understanding aberrant phase transitions in diseases.

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