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Mechanism of Membrane Activity of the Antibiotic Trichogin GA IV: A Two-State Transition Controlled by Peptide Concentration

Claudia Mazzuca ^*, Lorenzo Stella ^*, Mariano Venanzi ^*, Fernando Formaggio , Claudio Toniolo  and Basilio Pispisa ^*

^* Dipartimento di Scienze e Tecnologie Chimiche, Università di Roma Tor Vergata, 00133 Rome, Italy; and Istituto di Chimica Biomolecolare, Dipartimento di Scienze Chimiche, Università di Padova, 35131 Padua, Italy

Correspondence: Address reprint requests to Basilio Pispisa, Dipartimento di Scienze e Tecnologie Chimiche, Università di Roma Tor Vergata, Via Ricerca Scientifica, 00133 Rome, Italy. E-mail: pispisa{at}stc.uniroma2.it.

Synthetic fluorescent analogs of the natural lipopeptide trichogin GA IV were used to investigate the peptide position and orientation in model membranes. A translocation assay based on Förster energy transfer indicates that trichogin is associated to both the outer and inner leaflet of the membrane, even at low concentration, when it is not active. Fluorescence quenching measurements, performed by using water soluble quenchers and quenchers positioned in the membrane at different depths, indicate that at low membrane-bound peptide/lipid ratios trichogin lies close to the region of polar headgroups. By increasing peptide concentration until membrane leakage takes place, a cooperative transition occurs and a significant fraction of the peptide becomes deeply buried into the bilayer. Remarkably, this change in peptide position is strictly coupled with peptide aggregation. Therefore, the mechanism of trichogin action can be envisaged as based on a two-state transition controlled by peptide concentration. One state is the monomeric, surface bound and inactive peptide, and the other state is a buried, aggregated form, which is responsible for membrane leakage and bioactivity.

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