Revealing the Key Packing Features Determining the Stability of Peptide Bilayer Membrane

Short surfactant-like amphiphilic peptide, A₃K, resembling a surfactant with a hydrophobic tail (A₃) and a polar headgroup (K), is experimentally determined to form a membrane. Although the peptides are known to exist as β-strands, the exact packing architecture stabilizing the membrane is unknown. Earlier simulation studies have reported successful packing configurations through trial and error. In this work, we present a systematic protocol to identify the best peptide configurations for different packing patterns. The influence of stacking peptides in square and hexagonal packing geometry with the neighboring peptides in parallel and antiparallel orientations was explored. The best peptide configurations were determined from the free energy of bringing 2-4 peptides together as a bundle that can be stacked into a membrane. The stability of the assembled bilayer membrane was further investigated through molecular dynamics simulation. The role of peptide tilting, interpeptide distance, the nature and the extent of interactions, and the conformational degrees of freedom on the stability of the membrane is discussed. The consistency with the experimental findings suggests hexagonal antiparallel as the most relevant molecular architecture.