Membrane-active peptides: Binding, translocation, and flux in lipid vesicles

• Hypothesis: Free energy of insertion determines peptide translocation across membrane.
• Hypothesis: A threshold exists, about 20 kcal/mol, above which insertion is unlikely.
• The thermodynamics of peptide binding and insertion are reviewed and discussed.
• Peptide-induced graded and all-or-none fluxes are not simply related to translocation.
• Probability of peptide translocation seems to depend on the free energy of insertion.

Recently, new and improved methods have been developed to measure translocation of membrane-active peptides (antimicrobial, cytolytic, and amphipathic cell-penetrating peptides) across lipid bilayer membranes. The hypothesis that translocation of membrane-active peptides across a lipid bilayer is determined by the Gibbs energy of insertion of the peptide into the bilayer is re-examined in the light of new experimental tests. The original hypothesis and its motivation are first revisited, examining some of the specific predictions that it generated, followed by the results of the initial tests. Translocation is understood as requiring two previous steps: binding and insertion in the membrane. The problem of peptide binding to membranes, its prediction, measurement, and calculation are addressed. Particular attention is given to understanding the reason for the need for amphipathic structures in the function of membrane-active peptides. Insertion into the membrane is then examined. Hydrophobicity scales are compared, and their influence on calculations is discussed. The relation between translocation and graded or all-or-none peptide-induced flux from or into lipid vesicles is also considered. Finally, the most recent work on translocation is examined, both experimental and from molecular dynamics simulations. This article is part of a Special Issue entitled: Interfacially Active Peptides and Proteins. Guest Editors: William C. Wimley and Kalina Hristova.

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