Interaction of Gramicidin S and its Aromatic Amino-Acid Analog with Phospholipid Membranes

Abstract

To investigate the mechanism of interaction of gramicidin S-like antimicrobial peptides with biological membranes, a series of five decameric cyclic cationic beta-sheet-beta-turn peptides with all possible combinations of aromatic D-amino acids, Cyclo(Val-Lys-Leu-D-Ar1-Pro-Val-Lys-Leu-D-Ar2-Pro) (Ar identical with Phe, Tyr, Trp), were synthesized. Conformations of these cyclic peptides were comparable in aqueous solutions and lipid vesicles. Isothermal titration calorimetry measurements revealed entropy-driven binding of cyclic peptides to POPC and POPE/POPG lipid vesicles. Binding of peptides to both vesicle systems was endothermic-exceptions were peptides containing the Trp-Trp and Tyr-Trp pairs with exothermic binding to POPC vesicles. Application of one- and two-site binding (partitioning) models to binding isotherms of exothermic and endothermic binding processes, respectively, resulted in determination of peptide-lipid membrane binding constants (K(b)). The K(b1) and K(b2) values for endothermic two-step binding processes corresponded to high and low binding affinities (K(b1) >or= 100 K(b2)). Conformational change of cyclic peptides in transferring from buffer to lipid bilayer surfaces was estimated using fluorescence resonance energy transfer between the Tyr-Trp pair in one of the peptide constructs. The cyclic peptide conformation expands upon adsorption on lipid bilayer surface and interacts more deeply with the outer monolayer causing bilayer deformation, which may lead to formation of nonspecific transient peptide-lipid porelike zones causing membrane lysis.

Interaction of W-Substituted Analogs of Cyclo-RRRWFW with Bacterial Lipopolysaccharides: the Role of the Aromatic Cluster in Antimicrobial Activity

“…Except for the Dht-, Igl-, and Bal-containing cyclic peptides, peptide binding to POPC and POPC-POPG lipid bilayers is in good agreement with the nonclassical hydrophobic effect described for other CAPs (3,47,51). A comparable behavior has been reported for two W-containing gramicidin S analogs interacting with POPC (28).…”

Synergistic Activity of the Tyrocidines, Antimicrobial Cyclodecapeptides from Bacillus aneurinolyticus, with Amphotericin B and Caspofungin against Candida albicans Biofilms

“…GS is known to disrupt microbial membranes (47,48), and the tyrocidines have been shown to disrupt the membranes of bacteria (31,49), erythrocytes (32,50), and Neurospora organisms (51). We assessed the potential fungal membrane-disrupting activities of TrcA, TrcB and TrcC on in vitro-grown C. albicans biofilm cells using the fluorescent membrane-impermeable dye propidium iodide (Fig.…”

Effect of Ring Size on Conformation and Biological Activity of Cyclic Cationic Antimicrobial Peptides

“…Compared with GS14, the CD spectra of 13-meric peptides imply a decrease in the β-structure content of these peptides in buffer and lipid vesicles. Enhancement of negative ellipticities of peptides in both PC and PE/PG lipid systems indicate interaction of peptides with lipid membranes as well as their conformational changes (see above) 18,19. Similar to the peptides of the GS {10–12} group, there is a direct relation between the β-structure content of the peptides in lipid vesicles and their RTs and hemolytic activities –the lower the content of β-structure the lower the RTs and the weaker the hemolytic activities.…”