A hydrophobicity scale for the lipid bilayer barrier domain from peptide permeabilities: nonadditivities in residue contributions.

Abstract

Passive peptide transport across lipid membranes is governed by the energetics of partitioning into the ordered chain interior coupled with the rate of diffusion across this region. A hydrophobicity scale for peptide transfer into the barrier region of membranes derived from permeability coefficients would be useful to predict passive permeation of peptides across biomembranes and for determining the thermodynamics of peptide/protein insertion into the membrane interior. This study reports transport rates across large unilamellar vesicles (LUVs) composed of egg lecithin at 25 degrees C for a series of peptides having the general structure N-p-toluyl-(X)(n) (n =1-3), where X is glycine, alanine, or sarcosine. Apparent residue group contributions were calculated from permeability coefficients, P(RX), using the equation Delta(Delta G degrees )(X) = -RT ln(P(RX)/P(RH)). Multiple linear least-squares regression analysis performed for the set of 14 permeants yielded the best correlation (r(2) = 0.9993) when the following permeant descriptors were utilized: side-chain nonpolar surface area, number of -CONH- residues, number of toluyl-CON(Me)- residues, and number of other -CON(Me)- residues. The backbone -CONH- residue contribution in peptides, 4.6 kcal/mol, is significantly lower than that obtained for a single isolated -CONH- (>6 kcal/mol), suggesting a possible influence of intramolecular hydrogen bonding. Under closer scrutiny, Delta(Delta G degrees )(X) for the Ala and Gly residues decrease with increasing peptide length. The effect of N-methylation is also highly dependent on position and number of N-methyl groups on the molecule (Delta(Delta G degrees )(X) = -0.5 to -2.2 kcal/mol). These nonadditivities may be rationalized by considering the effects of peptide length and N-methylation on membrane-induced intramolecular hydrogen bonding leading to various folded conformations.