Figure 37.

Schematic overview of the possible interaction pathways of an antimicrobial peptide with a lipid bilayer. Possible thermodynamic states (either stable or metastable) are indicated by black labels, the major kinetic pathways connecting them by gray arrows and red labels. Short black arrows represent additional inter-conversion pathways. Outside the target membrane, peptide monomers and small aggregates exist in equilibrium. At the target membrane, the peptides bind to the interface (Adsorption). At the interface an equilibrium may exist between monomeric and polymeric aggregation states. For a symmetric bilayer, the asymmetric membrane bound state is not thermodynamically stable. Eventually the peptides will distribute equally between the two monolayer leaflets. This can occur via two alternative translocation pathways. In the non-leaky variant the peptides are able to cross the bilayer without the formation of a pore. In some cases, the intermediate transmembrane state is thermodynamically stable (e.g. hydrophobic peptides which adopt a transmembrane orientation). The key feature of many antimicrobial peptides is that they permeabilize the membrane following a leaky translocation pathway. Above a certain peptide– lipid ratio, the peptides insert into the bilayer to form a porated lamellar phase (Poration). A variety of different pore structures may be formed, including the barrel-stave, the toroidal and the disordered toroidal state. These separate states should be interpreted as extreme cases with mixed varieties of these models, and conversion between alternative states is likely to occur. The porated states can be stable themselves, but they can also be transient structures in the translocation pathway. In that case, once enough peptides are adsorbed at the opposing monolayer leaflet, the pores seal. On the other hand, increased accumulation of certain peptides may lead to a detergent-like disintegration of the membrane resulting in formation of non-lamellar, e.g. micellar, systems (solubilization pathway). Note that the secondary structure of the peptides could vary along the various pathways. The helical or random configurations drawn here are merely illustrative of these processes and should not be taken literally. Figure legend and image taken from reference 1389¹³⁸⁹.