Short surfactant-like amphiphilic peptides like A3K, resembling a surfactant with a hydrophobic tail (A3) and a polar headgroup (K) tends to self-assemble into a membrane. Such lamellar structure has potential applications as scaffold for tissue regeneration. Although alanine rich tetrapeptides are known to adopt polyproline II structure in dilute solution, they are determined to exist as β-strands in the membrane. The free energy calculations in implicit solvent revealed that only the peptides in β-strands can be packed closely with maximum number of hydrogen bonds, further validated through explicit solvent simulations with umbrella sampling. The association of β-strands, however, has to cross large energy barrier arising out of the entropic restriction on the intervening water molecules that form water mediated hydrogen bond bridges between the peptides.
Next, we determined the best packing configurations that can be stacked into a membrane from the free energy for formation of small bundles comprising 2-4 peptides. We explored the influence of stacking peptides in square and hexagonal packing geometry with the neighboring peptides in parallel and antiparallel orientations. The stability of the assembled bilayer membrane was subsequently investigated through molecular dynamics simulation. The consistency with the experimental findings suggests hexagonal antiparallel as the most relevant molecular architecture. From the stability analysis of tetrapeptides like A3K, A3D, KA3 and DA3, we found the peptides with charged residues at C-terminal can be packed efficiently and thereby resulted in more stable membrane than those with charged residues at N-terminal. The developed protocol is promising to systematically identify the possibility of a peptide sequence that could self-assemble into stable lamellar structure.
Publications:
1. Vidhya Ganesan and M. Hamsa Priya. Probing the Conformational Preference to β-Strand during Peptide Self-Assembly, J. Phys. Chem. B, 2023. doi: 10.1021/acs.jpcb.3c02327[/]

2. Vidhya Ganesan and M. Hamsa Priya, Revealing the Key Packing Features Determining the Stability of Peptide Bilayer Membrane, ACS Appl. Bio. Mater., 2023. doi: 10.1021/acsabm.2c00949