Pore formation and the key factors in antibacterial activity of aurein 1.2 and LLAA inside lipid bilayers, a molecular dynamics study.

Aurein 1.2 and LLAA are two antimicrobial peptides with different antibacterial activities (LLAA>Aurein 1.2), though their amino acid sequences are similar. In this manuscript, we study the key features for the different antibacterial activities of these peptides using molecular dynamics simulation. We find that in water, both peptides become disordered and LLAA is observed to have higher water-solubility, a feature which may contribute to enhancing its propensity to disrupt the bilayer and thus higher activity. Both peptides are also investigated while they are initially located inside lipid bilayer as a pre-formed vertical channel composed of five parallel copies of each peptide. LLAA demonstrates larger structural deviation from the initial helical structure and also more structural flexibility which is concluded to be a key feature in its stronger activity. In the presence of LLAA, the bilayer order is perturbed more pronouncedly and the number of water molecules penetrating into bilayer is higher. It is shown that stronger electrostatic interactions, more hydrophobic contacts and more hydrogen bonds between lipid and LLAA also lead to stronger activity of LLAA. The simulation results show instability of the barrel-stave pores for our peptides inside lipid bilayers.

Interaction of aurein 1.2 and its analogue with DPPC lipid bilayer.

Antibacterial peptides have potential as novel therapeutic agents for bacterial infections. Aurein 1.2 is one of the smallest antibacterial peptides extracted from an anuran. LLAA is a more active analogue of aurein 1.2. Antibacterial peptides usually accomplish their function by interacting with bacterial membrane selectively. In this study, we tried to find the reasons for the stronger antibacterial activity of LLAA compared with aurein 1.2. For this purpose, the interaction of aurein 1.2 and LLAA with dipalmitoylphosphatidylcholine (DPPC) was investigated by molecular dynamics (MD) simulation. In addition, the structure of peptides and their antibacterial activity were investigated by circular dichroism (CD) and dilution test method, respectively. MD results showed that LLAA is more flexible compared with aurein 1.2. Furthermore, LLAA loses its structure more than aurein 1.2 in the DPPC bilayer. A higher amount of water molecules penetrate into bilayer in the presence of LLAA relative to aurein 1.2. According to the antibacterial result that indicated LLAA is remarkably more active than aurein 1.2, it can be concluded that flexibility of the peptide is a determining factor in antibacterial activity. Probably, flexibility of the peptides facilitates formation of effective pores in the lipid bilayer.