Gramicidin

The linear peptide gramicidin forms prototypical ion channels specific for monovalent cations and has been extensively used to study the organization, dynamics and function of membrane-spanning channels. In recent times, the availability of crystal structures of complex ion channels has challenged the role of gramicidin as a model membrane protein and ion channel. This review focuses on the suitability of gramicidin as a model membrane protein in general, and the information gained from gramicidin to understand lipid-protein interactions in particular. Special emphasis is given to the role and orientation of tryptophan residues in channel structure and function and recent spectroscopic approaches that have highlighted the organization and dynamics of the channel in membrane and membrane-mimetic media.

The available information concerning the structure and location of the main binding site for sodium in the gramicidin A channel is reviewed and discussed. Results from molecular dynamics simulations using an atomic model of the channel embedded in a lipid bilayer are compared with experimental observations. The combined information from experiment and simulation suggests that the main binding sites for sodium are near the channel's mouth, approximately 9.2 A from the centre of the dimer channel, although the motion along the axis could be as large as 1 to 2 A. In the binding site, the sodium ion is lying off axis, making contact with two carbonyl oxygens and two single-file water molecules. The main channel ligand is provided by the carbonyl group of the Leu10-Trp11 peptide linkage, which exhibits the largest deflection from the ion-free channel structure.

Gramicidin S (GS), one of the oldest commercially used peptide antibiotics, is known for its robust antibacterial activity against both Gram-positive and Gram-negative bacterial strains. Although it was discovered well over 70 years ago, its clinical potential was limited to topical applications because of its high hemolytic activity. To overcome this side effect, significant efforts have been invested in the chase for GS analogues with high therapeutic index (e.g., high antimicrobial activity and low hemolytic activity) in the past decades. In this Perspective, the structural properties and biological profiles (including the recently discovered activities) of representative GS analogues designed by different approaches are described and analyzed. We also present how the general structure-activity relationships were established and how they could help in the design of more efficient GS analogues.