Hydrophobicity of N‐Acetyl‐Di‐ and Tripeptide Amides Having Unionizable Side Chains and Correlation with Substituent and Structural Parameters

Abstract

AbstractThe log P value of 53 N‐acetyl‐di‐ and tripeptide amides composed of amino acids having unionizable side chains was measured in a 1‐octanol/pH 7.0 aqueous buffer system. The factors governing the variations in the log P value among these protected peptides were quantitatively analyzed to formulate a correlation equation with free‐energy‐related physicochemical and substructural parameters. The log P value was governed by the sum of the hydrophobicity of side chains and the backbone as well as by the steric effects of side chain substituents on the relative solvation of the backbone CONH groups. The log P value was found to decrease by 0.6 log unit for the peptide bond, other factors being equal. For amino acids with polar side chains, the log P value was also affected by the “polar proximity factor” and/or intramolecular hydrogen bond formation in a way similar to that of zwitterionized peptides reported previously.