Are membrane proteins inside-out proteins? Proteins: Struct

ABSTRACT One of the central paradigms of structural biology is that membrane proteins are ‘‘inside-out’ ’ proteins, in that they have a core of polar residues surrounded by apolar residues. This is the reverse of the characteristics found in water-soluble proteins. We have decided to test this para-digm, now that sufficient numbers of transmem-brane a-helical structures are accessible to statistical analysis. We have analyzed the correla-tion between accessibility and hydrophobicity of both individual residues and complete helices. Our analyses reveal that hydrophobicity of residues in a transmembrane helical bundle does not correlate with any preferred location and that the hydro-philic vector of a helix is a poor indicator of the solvent exposed face of a helix. Neither polar nor hydrophobic residues show any bias for the exterior or the interior of a transmembrane domain. As a control, analysis of water-soluble helical bundles performed in a similar manner has yielded clear correlations between hydrophobicity and accessibil-ity. We therefore conclude that, based on the data set used, membrane proteins as ‘‘inside-out’ ’ proteins is an unfounded notion, suggesting that packing of a-helices in membranes is better understood by maximization of van der Waal’s forces, rather than by a general segrega-tion of hydrophobicities driven by lipid exclusion