I. Hydrophobic sequences form stable transbilayer alpha-helices
The thermodynamic cycle described by Popot and Engelman (1990) identifies the transmembrane alpha-helix as the most stable form of a long stretch of apolar amino acids that is in the presence of water and a lipid bilayer. The arguments leading to this conclusion are based upon straightforward estimates of the free energies for these equilibria.
Given that the net number of hydrogen bonds is not significantly changed upon going from a water-solvated helix to a water-solvated coil, the aqueous helix-coil transition is considered to be roughly isoenergetic.
The water-lipid partitioning of the helix is estimated to be on the order of 30 kcal/mole in favor of the lipid by virtue of the hydrophobic effect: exposing a 20 residue hydrophobic helix to water will require a dramatic reduction in water entropy.
The water-lipid partitioning of the coil is estimated to be 40 kcal/mole in favor of the water due to the loss of protein-water hydrogen bonds upon entering the bilayer.
The estimated energies for these three steps permit an estimate of the energy associated with the last step of thermodynamic cycle. Unfolding of the helices within the bilayer is estimated to be opposed by some 70 kcal/mole. Thus, once a hydrophobic sequence has been inserted into a membrane as a helix, it is energetically highly unfavorable for that helix to either leave the bilayer or to unfold within the bilayer.
II. Lateral association of transbilayer alpha-helices
The second part of the two stage model of membrane protein folding consists of the equilibrium between lipid solvated monomeric alpha-helices and associations of the helices into higher order states. The two states of the simplest example of this equilibrium, monomers and a homodimer, are cartooned below.
The formation of the dimer of helices results in an increase of helix-helix and
lipid-lipid interactions and a loss of helix-lipid interactions. The entropy of
the lipids is expected to increase, as depicted by the blue lipids released upon
dimerization; the entropy of the helices is expected to decrease. The value of
the equilibrium constant will depend on the magnitudes of these entropic terms
and on the enthalpic terms that arise from the detailed helix-helix, helix-lipid
and lipid-lipid contacts.
Note that helices that form part of polytopic transmembrane proteins may also be considered to fold in this manner. The association of the hydrophobic helices into a specific structure is expected to be influenced by the covalent linkages imposed by extramembraneous loops.