Binding modes of protegrin-1, a beta-strand antimicrobial peptide, in lipid bilayers

Abstract

Molecular dynamics (MD) simulations of the interactions of a beta-strand antimicrobial peptide, protegrin-1, with model lipid bilayers of different hydrophobic widths show that protegrin-1 possesses at least two distinct binding modes in the trans-membrane orientation. In one of the modes, three of the cationic arginine residues bind to one bilayer leaflet and the other three arginine residues bind to the opposite leaflet, while in the second binding mode, four arginines bind to one leaflet and two to the other. The existence of multiple binding modes is facilitated by the high conformational flexibility of the first four residues of the N-terminal region, with a sequence of RGGR. One of the binding modes causes a larger bilayer disruption than the other, and in either mode, the bilayer disruption is smaller for lipid membranes with smaller bilayer widths. Simulations of the self-assembly of initially random lipid/water mixtures in the presence of PG-1 peptides show that the system evolves into a bilayer, with a stable water pore spanning the two lipid leaflets. Lipid head groups and the PG-1 peptide stabilize the water pore.