The effect of metalation on antimicrobial piscidins imbedded in normal and oxidized lipid bilayers.

Abstract

Metalation of the N-terminal Amino Terminal Cu(ii)- and Ni(ii)-binding (ATCUN) motif may enhance the antimicrobial properties of piscidins. Molecular dynamics simulations of free and nickelated piscidins 1 and 3 (P1 and P3) were performed in 3 : 1 POPC/POPG and 2.6 : 1 : 0.4 POPC/POPG/aldo-PC bilayers (POPC, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine: POPG, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol; aldo-PC, 1-palmitoyl-2-(9'-oxo-nonanoyl)-sn-glycero-3-phosphocholine) bilayer models. Nickel(ii) binding decreases the conformation dynamics of the ATCUN motif and lowers the charge of the N-terminus to allow it to embed deeper in the bilayer without significantly changing the overall depth due to interactions of the charged half-helix of the peptide with the headgroups. Phe1⋯Ni2+ cation-π and Phe2-Phe1 CH-π interactions contribute to a small fraction of structures within the nickelated P1 simulations and may partially protect a bound metal from metal-centered chemical activity. The substitution of Phe2 for Ile2 in P3 sterically blocks conformations with cation-π interactions offering less protection to the metal. This difference between metalated P1 and P3 may indicate a mechanism by which peptide sequence can influence antimicrobial properties. Any loss of bilayer integrity due to chain reversal of the oxidized phospholipid chains of aldo-PC may be enhanced in the presence of metalated piscidins.