Secondary Structure-Encoded Control of Lipid Assembly by Radially Amphiphilic Peptides

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.