Protein-lipid interactions and the role of water.

The rigidity of the three-dimensional structure of a native protein is dependent on the network of hydrogen-bonded groups which provide the scaffolding for the other interactions. The structure is stabilized by the hydrophobic interactions of the nonpolar side chains. The latter are formed by the very unfavorable entropy change that occurs in water but not in less-polar solvents. It is unlikely that any solvent other than water can produce the same folding of a polypeptide chain to form the active native structure. Water plays a unique role, since it alone is responsible for the heat capacity changes observed when nonpolar groups are transferred from an aqueous to a nonaqueous environment, as exists in the interior of a protein. The need to juxtapose like groups and to avoid making contact among unlike groups imposes severe restrictions on the binding of small or large molecules to proteins. Consequently there must be proper pairing of polarities as well as close fitting of ligands for strong binding to occur. This is clearly evident from the x-ray studies of proteins containing subunits or prosthetic groups. The thermodynamic parameters observed in the most complex protein reactions--i.e., self-assembly systems--resemble rather well those observed in micelle association reactions or even in the solution of nonpolar gases in water. This interaction--hydrophobic--can be looked upon as the controlling reaction which stabilized the organized structures of most cellular entities aside from nucleic acids--i.e., membranes and organelles.