Quantitative analyses of the structure-hydrophobicity relationship for N-acetyl di- and tripeptide amides

The partition coefficient (P) of neutral species and the apparent partition ratio (P') at pH 7 of the ionized form were measured with the 1-octanol/water system for a number of N-acetyl di- and tripeptide amides having un-ionizable and ionizable side chains. Their log values were studied in terms of free-energy-related substituent and substructural parameters using regression analysis to give correlation equations of high quality physicochemically as well as statistically. The intrinsic hydrophobicity of side-chain substituents and their steric effect on the relative solvation of the backbone CONH groups were significant in determining the log P values of the un-ionizable acetyl peptide amides. For the log P value of peptides with polar side-chain substituents, respective indicator variable terms were required to account for the sum of specific effects of substituents such as intramolecular hydrogen-bond formation and the "polar proximity factor" for augmentation of the hydrophobicity. For the log P'(pH 7) value of basic and acidic peptides, the ability of counterionic species to form ion-pairs, the change in the apparent hydrophobicity of ionizable groups from the intrinsic value for their nonionized forms, the effect of ion-pairing itself, and other effects were additionally considered. From the regression coefficients of the parameter terms in correlation equations an effective hydrophobicity index was defined for each side chain, and the application and its limitation were suggested.