Stepwise disassembly of supramolecular structures triggered by specific protein binding

Supramolecular assemblies that can spontaneously disassemble in response to specific protein binding provide a powerful platform for sensing and targeted delivery. This concept has been previously demonstrated using a peptide-based amphiphilic polymer (P1) that consists of both hydrophobic M1 and hydrophilic M2 and M3 side chains and presents a specific ligand for protein bovine carbonic anhydrase II (bCA-II). To further understand the molecular forces and mechanism of the assembly and disassembly of P1, we developed a coarse-grained modeling framework for direct simulation of the dynamic polymer-unimer equilibrium of amphiphilic peptide nanoassembly. The results show that P1 unimers initially self-assemble into small micelles, which are capable of encapsulating hydrophobic cargos such as the dye molecule DiI. The micelles subsequently aggregate into larger multicore nanostructures. Notably, the micelle architecture persists within the larger aggregates, with the hydrophobic M1 side chains forming distinct cores. The simulations further show that introduction and binding of bCA-II to the M3 side chains, which contain the specific ligand, lead to a disassembly process. Our simulations revealed that bCA-II binding causes a stepwise disassembly of the aggregates. First, the micelle-micelle interfaces are replaced by micelle-water interfaces, with minimal exposure of individual M1-concentrated hydrophobic cores. Complete disassembly occurs only when multiple bCA-II molecules bind to a single micelle, leading to the breakdown of the hydrophobic core and the subsequent release of encapsulated DiI molecules. This stepwise disassembly mechanism underscores the intricate balance between structural stability and responsiveness in these supramolecular assemblies. Our findings provide new insights into the design of smart materials for biomedical applications, where controlled release mechanisms are essential. The ability to fine-tune the assembly and disassembly processes through specific molecular interactions opens many new possibilities for the development of responsive drug delivery systems and biosensors.