Computational methods to estimate passive membrane permeability coefficients of organic molecules, including peptides, would be valuable in understanding various biological processes associated with molecular transport across cell membranes and in reducing the time required for screening developability properties of new drug candidates. This study explores the suitability of fragment-based linear free energy relationships (LFERs) to predict lipid bilayer permeability coefficients and decadiene/water partition coefficients of a set of 47 model permeants. The inclusion of mono-, di-, and tripeptides comprised of glycine, alanine, and sarcosine residues in the database presented added challenges due to the apparent lack of independence of the contribution of the backbone amide residue in peptides to the free energy of transfer (Delta(Delta G degrees ) -CONH-) from water to organic solvents or to the bilayer barrier domain. In order to elucidate the impact of neighboring group effects on Delta(Delta G degrees ) -CONH-, a series of RGZ glycine (G)-containing peptides having an additional -NHCH 2CO- residue compared to their RZ counterparts were synthesized, where R = acetyl (Ac-), 4-carboxymethylphenyl acetyl (CMPA-), or 4-methylphenyl acetyl (MPA-), and Z = -OH, -OMe, -NHMe, or -NMe 2. While variations in R had no significant impact on Delta(Delta G degrees ) -Gly-, significant effects of neighboring ( i + 1) Z substituents at the C-terminus were revealed both in studies of the relative transport of RGZ/RZ compound pairs across DOPC bilayers and partitioning between water and 1,9-decadiene (a bulk solvent with a similar chemical selectivity to the barrier domain of DOPC/eggPC bilayers). The proximity effects decline when the bulk solvent used in partitioning studies is 1-octanol, suggesting a possible role for intramolecular hydrogen bonding in the observed nonadditivity of Delta(Delta G degrees ) -CONH-. A new LFER for predicting decadiene/water partition coefficients was developed by including the contributions of polar fragments, total nonpolar surface area of nonpolar fragments, and correction factors to account for the effects of i + 1 substituents in peptides on the group contribution of the peptide backbone amide bond to the free energy of transfer. This LFER could be used to predict lipid bilayer permeability coefficients by including an additional term to account for the added influence of molecular size on bilayer permeability.