Hydrophobicity of Di‐ and Tripeptides Having Unionizable Side Chains and Correlation with Substituent and Structural Parameters

Abstract

AbstractAfter establishing experimental conditions to obtain a reliable partition ratio, P', we measured the value of 59 di‐ and tripeptides composed of amino acids having unionizable side chains in a 1‐octanol/pH 7.0 aqueous phosphate buffer system in order to approximate the true partition coefficient. We then formulated an equation correlating the variations of log P' (pH 7) among peptides with free‐energy‐related physicochemical parameters for the side chain substituents and substructures. The log P' value of di‐ and tripeptides is governed by the sum of the hydrophobicity of the peptide backbone and side chains as well as by the steric effect of side chain substituents on the relative solvation of backbone and terminal functional groups. For peptides containing amino acids with polar side chains, the log P' value is higher than that predicted by these effects. The difference is larger as the polar heteroatom in side chains gets closer to the backbone. This may correspond to the “polar proximity factor” for reductions of hydrophilicity observed when polar groups are crowded together. For the side chain of serine and threonine, the difference is even higher than that expected by the polar proximity effect, presumably due to intramolecular hydrogen bond formation.