Hydrophobic effect in protein folding

Lins L, Brasseur R. The hydrophobic effect in protein folding. FASEB J 1995 9 535-540. 

Spolar, R., et al. (1989). Hydrophobic Effect in Protein Folding and Other Noncovalent Processes Involving Proteins, PNAS 86 8382-8385. 

The van der Waals model of monomeric insulin (1) once again shows the wedge-shaped tertiary structure formed by the two chains together. In the second model (3, bottom), the side chains of polar amino acids are shown in blue, while apolar residues are yellow or pink. This model emphasizes the importance of the hydrophobic effect for protein folding (see p. 74). In insulin as well, most hydrophobic side chains are located on the inside of the molecule, while the hydrophilic residues are located on the surface. Apparently in contradiction to this rule, several apolar side chains (pink) are found on the surface. However, all of these residues are involved in hydrophobic interactions that stabilize the dimeric and hexameric forms of insulin. 

How does the hydrophobic effect favor protein folding Some of the amino acids that make up proteins have nonpolar groups. These nonpolar amino acids have a strong tendency to associate with one another inside the interior of the folded protein. The increased entropy of water resulting from the interaction of these hydrophobic amino acids helps to compensate for the entropy losses inherent in the folding process. 

Ensembles 600 Enterokinase 480 Enthalpy 55 activation 56, 545-547 protein folding 509 -512 specific heat effects 511, 545 - 547 Enthalpy-entropy compensation 346 Enthalpy versus entropy in protein folding 509-512, 587, 599 Entropy 55, 68-72 activation 56, 545 -547 binding 324, 345 Boltzmann equation 510 chelate effect 345 configurational 510 configurational entropy of loops 535 effective concentration 68-72 equilibria on enzyme surface 118 hydrogen bond 338 hydrophobic bond 332, 510 importance in enzyme catalysis 72 importance in enzyme-substrate binding 72... 

Of equal importance, the use of RPC and HIC techniques provides a very powerful avenue to explore the molecular basis of the hydrophobic effect per se that these biomacromolecules exhibit. Since the time of the initial attempts, commencing over 50 years ago, to exploit the hydrophobic effect as part of robust separation procedures, RPC and HIC have thus come to assume a dominant position for the isolation and analysis of many proteins and now represent the techniques par excellence for the purification and analysis of polypeptides prepared by solid- or solution-phase synthetic procedures. Equally, these techniques provide an opportunity to explore the role of the hydrophobic effect in the stabilization and folding of proteins and polypeptides, the molecular forces that are involved in these processes, the thermodynamics of their interaction with relatively well-defined nonpolar surfaces, and the biophysics of peptide or protein nonpolar interactions in general. 

The hydrophobic effect is important in protein folding. This has been shown by synthesizing proteins with specific sequences of amino acids. It was observed that these proteins folded into the designed conformation with hydrophobic groups in the interior and polar groups on the surface. 

Proteins contain many nonpolar side chains. These side chains are repelled by water and tend to associate with one another on the inside of a folded protein molecule, out of contact with water. The tendency of nonpolar side chains to collect out of contact with the solvent is called the hydrophobic effect. The hydrophobic interactions in proteins are similar to those in the micelle of a soap (Section 21.5) or the bilayer of lipids in membranes. Hydrophobic interactions among nonpolar side chains in proteins are weak, but abundant, and are primarily responsible for maintaining the folded conformation of a protein. 

The major driving force in protein folding is the hydrophobic effect. This is the tendency for hydrophobic molecules to isolate themselves from contact with water. As a consequence during protein folding the hydrophobic side chains become buried in the interior of the protein. The exact physical explanation of the behavior of hydrophobic molecules in water is complex and can best be described... 

---