Pathway‐Selection for Programmable Assembly of Genetically Encoded Amphiphiles by Thermal Processing

Engineering the fate of supramolecular assemblies by heat treatment (i. e., using thermal preparative pathways) remains challenging and a largely ad hoc process. The rational design of such trajectories requires precise manipulation of the strength of molecularly encrypted interactions along an assembly path defined by changes in free energy as a function of temperature. Here, we use temperature‐triggered liquid–liquid phase separation of proteins to program the nano‐ and mesoscale assembly of a genetically encoded amphiphile – a post‐translationally lipidated protein – along user‐defined thermal trajectories. This molecularly defined pathway was used to funnel thermal energy into the system to direct building blocks to a previously inaccessible region of the energy landscape, and to synthesize two‐dimensional nanomaterials with sophisticated structures, such as braids and toroids. Because proteins’ phase boundaries and transition are programmable at the sequence‐level, our strategy opens new horizons to expand the structural hierarchy and functional landscape of protein‐based materials. Low‐fat high‐protein recipes for nanosynthesis: Temperature‐triggered liquid–liquid phase separation of a lipidated protein is leveraged to direct amphiphilic building blocks across the supramolecular energy landscape. This pathway‐dependent thermal processing is used to synthesize two‐dimensional nanomaterials with complex morphologies, such as toroids.