Investigations into the ability of an oblique α-helical template to provide the basis for design of an antimicrobial anionic amphiphilic peptide

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AP1 (GEQGALAQFGEWL) was shown by theoretical analysis to be an anionic oblique-orientated α-helix former. The peptide exhibited a monolayer surface area of 1.42 nm2, implying possession of α-helical structure at an air/water interface, and Fourier transform infrared spectroscopy (FTIR) showed the peptide to be α-helical (100%) in the presence of vesicle mimics of Escherichia coli membranes. FTIR lipid-phase transition analysis showed the peptide to induce large decreases in the fluidity of these E. coli membrane mimics, and Langmuir–Blodgett trough analysis found the peptide to induce large surface pressure changes in monolayer mimics of E. coli membranes (4.6 mN·m−1). Analysis of compression isotherms based on mixing enthalpy (ΔH) and the Gibbs free energy of mixing (ΔGMix) predicted that these monolayers were thermodynamically stable (ΔH and ΔGMix each negative) but were destabilized by the presence of the peptide (ΔH and ΔGMix each positive). The peptide was found to have a minimum lethal concentration of 3 mM against E. coli and was seen to cause lysis of erythrocytes at 5 mM. In combination, these data clearly show that AP1 functions as an anionic α-helical antimicrobial peptide and suggest that both its tilted peptide characteristics and the composition of its target membrane are important determinants of its efficacy of action.

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