Interhelical hydrogen bonding drives strong interactions in membrane proteins

Polar residues in transmembrane alpha-helices may strongly influence the fo lding or association of integral membrane proteins. To test whether a motif that promotes helix association in a soluble protein could do the same wit hin a membrane, we designed a model transmembrane helix based on the GCN4 l eucine zipper. We found in both detergent miscelles and biological membrane s that helix association is driven strongly by asparagine, independent of t he rest of the hydrophobic leucine and/or valine sequence. Hydrogen bonding between membrane helices gives stronger associations than the packing of s urfaces in glycophorin A helices, creating an opportunity to stabilize stru ctures, but also implying a danger that non-specific interactions might occ ur. Th us, membrane protei ns may fold to avoid exposure of strongly hydrog en bonding groups at their lipid exposed surfaces.