The effect of membrane curvature on the conformation of antimicrobial peptides: implications for binding and the mechanism of action

Abstract

Short cationic antimicrobial peptides (AMPs) are believed to act either by inducing transmembrane pores or disrupting membranes in a detergent-like manner. For example, the antimicrobial peptides aurein 1.2, citropin 1.1, maculatin 1.1 and caerin 1.1, despite being closely related, appear to act by fundamentally different mechanisms depending on their length. Using molecular dynamics simulations, the structural properties of these four peptides have been examined in solution as well as in a variety of membrane environments. It is shown that each of the peptides has a strong preference for binding to regions of high membrane curvature and that the structure of the peptides is dependent on the degree of local curvature. This suggests that the shorter peptides aurein 1.2 and citropin 1.1 act via a detergent-like mechanism because they can induce high local, but not long-range curvature, whereas the longer peptides maculatin 1.1 and caerin 1.1 require longer range curvature to fold and thus bind to and stabilize transmembrane pores.

Fig. 1

The helix fraction (Helix_F) as a function of simulation time for the peptides aurein 1.2 (a), citropin 1.1 (b), maculatin 1.1 (c) and caerin 1.1 (d) in different environments. The environments were: water (1), 50% v/v trifluroethanol (TFE) (2), in the presence of a DPC micelle (3), in the presence of a POPC bilayer containing a pore (4) and in the presence of a planar DMPC bilayer (5). The triangles, circles and stars denote three independent simulations

Fig. 2

The secondary structure of citropin 1.1 as a function of simulation time in: water (a), TFE (b), bound to a DPC micelle (c), bound to a POPC bilayers containing a pore (d) and bound to a planar DMPC bilayer (e). The structure on the right is the final conformation of the peptide after 200 ns of simulation in the corresponding environment

Fig. 3

The secondary structure of maculatin 1.1 as a function of simulation time in: water (a), TFE (b), bound to a DPC micelle (c), bound to a POPC bilayers containing a pore (d) and bound to a planar DMPC bilayer (e). The structure on the right is the final conformation of the peptide after 200 ns of simulation in the corresponding environment

Fig. 4

The structures of selected peptides in specific lipid environments after 200 ns of simulation: citropin 1.1 bound to a DPC micelle (a), maculatin 1.1 bound to a DPC micelle (b); citropin 1.1 bound to a toroidal pore within a POPC bilayer (c); caerin 1.1 bound to a toroidal pore within a POPC bilayer (d). The peptide backbone is shown in magenta (cartoon representation); the molecular surface of hydrophobic and hydrophilic residues is shown in orange and blue, respectively. Lipid head groups are in blue and lipid tails in grey. In a and b the tails of lipids that cover the peptide are highlighted in orange