Precise control over the hierarchical superstructures of peptides and lipids is critical for various biological processes. While the secondary structure of peptides plays a pivotal role in modulating interactions between peptides and lipids during self-assembly, the underlying physical principles that govern the dynamics and kinetics of the assembly of hierarchical superstructures remain poorly understood. Here, we study secondary structure-encoded control of lipid assembly by radially amphiphilic peptides (RAPs), and we find that the RAP helicity promotes the formation of thermodynamically stable layer-by-layer superstructures. The free-energy landscapes of RAPs/POPG assembly reveal two distinct pathways, a singular-layer pathway and a layer-by-layer pathway. The helicity gives rise to the strong kinetic preference of the layer-by-layer pathway, which directs toward the layer-by-layer state compared with the singular-layer pathway, as evidenced by the significantly lower enthalpic barrier for the α-helical RAPs system transitioning from the on-path intermediate state of porous-rich layer to the defect-free layer-by-layer state. Insights into the interplay between RAPs and POPG lipids show that the α-helical RAPs expose a greater hydrophilic surface, which enhances the fluidity of both the peptides and the lipids. This increased fluidity facilitates the disruption of stalk structures in the cross-cylinder and porous-rich layer states, thereby promoting escape from the long-lived metastable states. In summary, our results reveal a comprehensive understanding of the secondary structure-encoded control of lipid assembly by RAPs, and they offer valuable theoretical guidance for the design of hierarchical superstructures.
Huang et al. (Mon,) studied this question.