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Modulation of the binding of signal peptides to lipid bilayers by dipoles near the hydrocarbon-water interface.

Interactions between signal (leader) sequences and membranes are critical to protein insertion and translocation across membranes. In this paper, circular dichroism, tryptophan fluorescence, electrophoretic mobility, dipole potential, and binding measurements were used to study the interaction of the signal sequence of the Escherichia coli LamB protein with various lipid bilayers. By modifying specific chemicophysical properties of both the signal sequence and bilayer, we analyzed some of the key factors underlying peptide-lipid interactions. We synthesized three analogues of the LamB signal peptide differing in their net charge (-2 to +4) and studied their binding to bilayers containing combinations of neutral lipids [egg phosphatidylcholine (EPC), sphingomyelin, cholesterol, ketocholesterol, and nitroxide-containing phospholipid] and a charged lipid (phosphatidylserine). All three peptides bound to EPC bilayers and underwent a random coil to alpha-helix transition upon binding. Microelectrophoresis experiments revealed that both the N and C termini were near the outer surface of the bilayer, suggesting that the peptides adopted a "hammock" configuration with both termini exposed to the aqueous phase and the core of the alpha-helix located near the hydrocarbon-water interface. The binding of these LamB peptides was not markedly dependent on the bilayer area per molecule, compressibility modulus, or dipole potential, but did depend on the charge of the peptide and bilayer interfacial region. Moreover, the binding of LamB peptides was essentially eliminated in bilayers composed of phospholipids with a nitroxide moiety at the 7 position in one of their acyl chains or in EPC bilayers containing equimolar ketocholestanol. We propose that the incorporation of nitroxide or ketone groups into the hydrocarbon region near the lipid headgroup increases the effective width of the hydrophilic interfacial region and prevents some of the hydrophobic amino acids in the alpha-helix from reaching the nonpolar hydrocarbon core, thereby diminishing the free energy of partitioning and inhibiting peptide binding. These results point to an important role for interfacial dipoles in peptide-lipid interactions.