Hydrophobicity regained

Abstract

A widespread practice is to use free energies of transfer between organic solvents and water (Δ Gtransfer°) to define hydrophobicity scales for the amino acid side chains. A comparison of four Δ Gtransfer° scales reveals that the values for hydrogen‐bonding side chains are highly dependent on the non‐aqueous environment. This property of polar side chains violates the assumptions underlying the paradigm of equating Δ Gtransfer° with hydrophobicity or even with a generic solvation energy that is directly relevant to protein stability and ligand binding energetics. This simple regaining of the original concept of hydrophobicity reveals a flaw in approaches that use Δ Gtransfer° values to derive generic estimates of the energetics of the burial of polar groups, and allows the introduction of a “pure” hydrophobicity scale for the amino acid residues.