Lipid−Peptide Communication in Fluid Bilayers

Abstract

The influence of channel and nonchannel forms of gramicidin A (c-gA and nc-gA, respectively) on the mixing behavior of phospholipids derived from 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) has been examined in the physiologically relevant fluid phase by means of nearest-neighbor recognition methods (Davidson, S. K. M.; Regen, S. L. Chem. Rev. 1997, 97, 1269). Thus, when disulfide-based dimers were allowed to undergo monomer exchange at 60 °C in the presence of 5 mol % of nc-gA, the molar ratio of heterodimer to each homodimer was 1.55 ± 0.07; replacement of 50% of the exchangeable monomers with 1, 2-dipalmitoyl-sn-glycero-3-phosphocholine (a chemically inert diluent having an intermediate chain length and hydrophobicity) eliminated the ability of nc-gA to induce NNR. In sharp contrast, the presence of c-gA, at concentrations as high as 9 and 17 mol %, left the phospholipids in a randomly arranged state. The ability of gramicidin A to “communicate” its conformation to the surrounding phospholipids implies that lateral transmission of conformational information should also be possible between lipids and proteins in biological membranes.

Dynamic Combinatorial Chemistry

“…Thus analysis of the product mixture allows conclusions to be drawn regarding the way the thiol-modified phospholipid (or sterol molecules) are organized in the bilayer. Specific topics that have been addressed using this approach include the influence of cholesterol, ,− the nature of the headgroup, − unsaturation of the alkyl chains, , the nature of the linkage between the glycerol unit and the alkyl chains (ester or ether), , sphingolipids, , headgroup hydration, peptides, , the extent of cooperativity in demixing, and most recently the extent of trans-bilayer organization. − Because a comprehensive overview over this extensive body of work is beyond the scope of this review, we will here only mention one particularly appealing recent example that illustrates an interesting type of template effect on lipid organization. The Regen lab has studied the equilibrium among disulfide dimers 98 − 100 (Scheme ) in the absence and presence of the fixed dimers 101 and 102 in order to assess the extent of trans-bilayer organization.…”

Cholesterol-Modulated Lipid−Peptide Communication in Fluid Bilayers

“…For this purpose, we have measured the mixing behavior of exchangeable monomers of 1,2-dimyristoyl- sn -glycerol-3-phosphoethanolamine and 1,2-distearoyl- sn -glycerol-3-phosphoethanolamine ( 1 and 2) in vesicles containing the channel (c-gA) and nonchannel (nc-gA) forms of gramicidin A, plus varying concentrations of cholesterol. In previous studies, we have shown that nc-gA (but not c-gA) induces nonideal mixing of these monomers, where like monomers become favored nearest neighbors . A detailed examination of this system has further indicated that the driving force for nonideal mixing involves the formation of a complex between nc-gA and the longer, exchangeable monomer units of 2 .…”

Dynamic Combinatorial Chemistry: Ligands for Biomolecules

“…In an interesting study, gramicidin A, a bacterial channel -forming antibiotic, was used to infl uence the equilibrium distribution of a DCL -like system [53] . A mixture of two disulfi de -based phospholipids was used to form vesicles.…”