The hydrophobicity threshold for peptide insertion into membranes

Peptides designed as model transmembrane segments are shown to insert spontaneously from water into micellar membranes only when their mean residue hydrophobicity is equivalent to or greater than a polyalanine segment. By using circular dichroism-derived peptide helicity as a probe of membrane insertion and correlating high-performance liquid chromatography-derived peptide hydrophobicity with helicity, we were able to determine quantitatively the hydrophobicity threshold. This analysis allows (1) assignment of hydropathy indices to the 20 commonly occurring amino acids and (2) assessment of the membrane insertion potential of a given transmembrane segment as “all-or-nothing,” depending upon whether its segmental hydrophobicity, calculated from the indices of its component amino acids, surpasses or fails to meet the minimum hydrophobicity requirement for integration into the membrane. The minimum hydrophobicity threshold was found to be satisfied by >96% of over 5000 transmembrane segments derived from a database of single- and multispanning intrinsic membrane proteins. When applied in vivo , the notion of “threshold hydrophobicity” would allow the selective incorporation of transmembrane segments into the lipid bilayer during the biosynthetic translocation process without the requirement of any additional expenditure of energy.