Direct Determination of the Membrane Affinities of Individual Amino Acids

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Abstract
Amino acids have distinct lipid bilayer affinities which influence the insertion and topology of membrane-bound polypeptides and proteins. To measure membrane affinities, 14 uncharged amino acids were introduced individually at a guest site in a 25-residue peptide derived from the membrane-binding presequence of yeast cytochrome c oxidase, and the peptides were labeled with a nitroxide spin-label. The free energies of transfer from phospholipid bilayers to water (ΔΔGbilayer) were determined directly by examination of partitioning into phospholipid bilayers using electron paramagnetic resonance. The ΔΔGbilayer values are in agreement with hydrophobicities assessed from 1-octanol−water partitioning of N-acetyl amino acid amides [Fauchere, J.-L., & Pliska, V. (1983) Eur. J. Med. Chem. 18, 369−375; Eisenberg, D., & McLachlan, A. (1986) Nature319, 199−203] and quantitatively demonstrate the role of the hydrophobic effect in membrane−protein interactions.