Lipophobicity and the residue environments of the transmembrane alpha-helical bundle

We present a statistical analysis of residue environment preferences along the membrane normal in helical transmembrane (HTM) proteins, based on an up-to-date nonredundant set of protein structures. Distinct amino acid residue propensities were revealed, both in terms of lipid accessibility and depth within the lipid bilayer, highlighting their potential usefulness for alignment and modelling of membrane proteins. Using the propensities in the HTM proteins, new lipophobicity scales (LIPS) were derived for the lipid bilayer interface (LI) and the hydrocarbon core (HC) regions of the membrane, measuring the tendencies of different amino acids to occupy protein-buried or lipid-exposed positions. The LIPS for LI and HC resemble some of the existing LIPS such as kPROT, TMLIP2, and LA but our new scales were derived by using more comprehensive information than any of the existing scales and are distinct overall. Effective free energies of transfer derived from the LIPS showed a good correlation with a semi empirical scale for the transfer energies from the interface of palmitoyloleoylphosphocholine (POPC) bilayers to ocatanol (Delta WW(ioct)). The new scales also predicted the lipophobic effect in the LI to be smaller than the hydrophobic effect governing the folding of globular proteins, consistent with theory and experiment. These results provided a coherent description of lipophobicity in the distinct layers of the membrane and gave clarity to the widely discussed notion of whether membrane proteins can be regarded as "inside out" of globular proteins.