The membrane activity of the antimicrobial peptide caerin 1.1 is pH dependent.

Abstract

Histidine-rich antimicrobial peptides (AMPs) are an important class of membrane-active peptides that can provide a scaffold to induce pH-sensitive interactions with cell membranes. The Australian tree frog AMP, caerin 1.1 (Cae-1), has three histidine residues, which modify the interactions with neutral and negatively charged lipid systems. NMR and MD simulations showed that in an acidic environment in comparison to physiological conditions, Cae-1 induced greater perturbation of the lipid dynamics and water penetration into the membrane interior. Lipid packing, chemical environment, and dynamics of the phospholipid headgroup were monitored using 31P solid-state NMR. In particular, the CODEX technique revealed that Cae-1 has a large impact on the slow re-orientation of the lipids. 2H solid-state NMR showed that Cae-1 ordered the acyl chains across the hydrophobic core. Interestingly, titration of the paramagnetic Mn2+ into the lipid-AMP systems resulted in extensive quenching of the 13C solid-state NMR signals of the lipid headgroup and acyl chain carbons. These results supported the MD results that showed Cae-1 was mainly inserted within the lipid bilayer structure of both neutral and negatively charged membranes, with the charged residues dragging the water and phosphate groups inwards. This could be an early step in the mechanism of membrane disruption by histidine-rich AMPs and indicated that Cae-1 is potentially forming toroidal pores in bilayers of neutral and negatively charged lipid membranes, especially under acidic conditions.