Functional group contributions to peptide permeability in lipid bilayer membranes : the role of peptide conformation and length

Successful prediction of drug transport rates across biological membranes and partitioning in the body based on structure alone requires an understanding of the factors controlling passive diffusion across lipid bilayer membranes as this is the major route of entry. The barrier domain solubility-diffusion model predicts that passive diffusion of small polar molecules across egg lecithin bilayers is controlled by partitioning from water into the ordered acyl chain region. The lipid bilayer permeability coefficient (P) can be predicted from the organic solvent/water partition coefficient (PC) provided that an appropriate bulk organic solvent having the same physicochemical properties as the barrier domain is chosen. The appropriate bulk solvent is one that gives a slope of 1.0 in a plot of log(P) versus log(PC). Apparent substituent contributions to the free energy of transfer from water into the barrier domain (?(?G°) P = -RTln(P RX /P RH )) were determined by comparing permeability coefficients of substituted compounds (P RX ) to reference (P RH ) compounds using large unilamellar vesicles (LUVs) composed of egg lecithin. Independence of group contributions was verified by evaluating the effect of substitution at the ?-methyl position of both p -toluic and p -methylhippuric acid. These studies demonstrated that 1,9-decadiene precisely mimics the barrier domain. As the permeants were increased in size the functional group independence was lost as the residue (?(?G°) P values decreased as size increased. Residue contributions varied considerably: glycine, 2510-4490 cal/mol, (3460 average); alanine, 2800-3680 cal/mol (3240 average); sarcosine, 1250-3990 cal/mol (2270 average); N-methylation (-2220 to -288 cal/mol, (-1300 average)). The variability suggest that predictions of membrane permeability using whole residue contributions may be unreliable without considering intramolecular hydrogen-bonding and the various conformations which may exist within membranes. Molecular dynamics simulations were performed in water and 1,9-decadiene. These simulations provided evidence for more prevalent intramolecular hydrogen bonding interactions in 1,9-decadiene. A strong correlation of log(P) with log(PC 1,9-decadiene ) was observed even for peptides that fold in 1,9-decadiene. This suggests that the non-additivities exhibited in functional group contributions generated from permeability coefficients are also evident in bulk solvent/water partitioning. This supports the hypothesis that intramolecular hydrogen-bonding is a primary factor contributing to nonindependence.