Thermodynamics of Protein Folding

Folding of a polypeptide chain is a thermodynamically favored process. Individual thermodynamic components relating to folding include the following:

> Conformational Entropy - production of a single folded molecule from a multitude of random-coil conformations involves a decrease in randomness and thus a decrease in entropy. From G = H - TS, a negative S makes a positive contribution to G. This must be offset by either a negative H or some other increase in entropy as a result of folding.

> Internal Interactions - energetically favorable interactions between groups within the folded molecule. These interactions, which include charge-charge, internal hydrogen bonding, and van der Waals interactions, are the major source of the negative H of folding.

> > Charge-Charge Interactions - occur between positively and negatively charged side chain groups. Interactions between oppositely charged groups (attraction) are also called salt bridges. Repulsive forces between like charges can also contribute to the overall structure.

> > Internal Hydrogen Bonds - interactions between amino acid side chains that are either good hydrogen bond donors (such as the hydroxyls of serine or threonine) or good acceptors (such as the carbonyl oxygens of asparagine or glutamine) (Figure 6.21). Though hydrogen bonds are relatively weak, the large number of them can make a considerable contribution to stability.

> > van der Waals Interactions - weak interactions between uncharged molecular groups in the tightly packed environment of a folded protein. The contributions of these interactions to the negative enthalpy of folding is diminished by giving up favorable interactions with water via folding.

> The Hydrophobic Effect - interactions between hydrophobic regions of a protein, which actually increase entropy by destroying the ordered clathrate structures of water around these residues in the unfolded state. The hydrophobic effect is sometimes incorrectly called hydrophobic bonding. Table 6.4 shows numerical values assigned to the relative hydrophobicities of the amino acids. In Table 6.3, the hydrophobic effect can be seen by the more positive S values for cytochrome c and myoglobin.

Figure 6.22 helps illustrate the relative contributions to the free energy of folding of globular proteins.

See also: Secondary Structure (General), Globular Proteins, Factors Determining Secondary and Tertiary Structure, Clathrate Structure of Water, Enthalpy, Entropy, Interplay of Enthalpy and Entropy