Protein folding stabilizing forces

Noncovalent Forces Stabilizing Protein Structure. Much of protein engineering concerns attempts to alter the stmcture or function of a protein in a predefined way. An understanding of the underlying physicochemical forces that participate in protein folding and stmctural stabilization is thus important. 

Upon biosynthesis, a polypeptide folds into its native conformation, which is structurally stable and functionally active. The conformation adopted ultimately depends upon the polypeptide s amino acid sequence, explaining why different polypeptide types have different characteristic conformations. We have previously noted that stretches of secondary structure are stabilized by short-range interactions between adjacent amino acid residues. Tertiary structure, on the other hand, is stabilized by interactions between amino acid residues that may be far apart from each other in terms of amino acid sequence, but which are brought into close proximity by protein folding. The major stabilizing forces of a polypeptide s overall conformation are ... 

The forces that stabilize amyloid fibrils include specific hydrogen bonding, electrostatic interactions, n-n stacking, and hydrophobic interactions. Importantly, similar types of interactions stabilize the functional native structures of protein molecules (Anfinsen, 1973 Dill, 1990 Dobson and Karplus, 1999 Kauzmann, 1959). In this sense, the conditions that favor native protein folding might also be manipulated to facilitate the formation of amyloid fibrils. 

The balance of favorable minimization of hydrophobic area and unfavorable reduction of conformational states upon folding will determine the stability of the protein. As these forces tend to be large and comparable in magnitude, the free enthalpy of formation of a protein is the sum of two large opposing forces and may thus be negative or positive. In any case, a folded and catalytically active protein is always just a few kilojoules away from instability. 

Hydrophobic forces The hydrophobic effect is the name given to those forces that cause nonpolar molecules to minimize their contact with water. This is clearly seen with amphipathic molecules such as lipids and detergents which form micelles in aqueous solution (see Topic El). Proteins, too, find a conformation in which their nonpolar side chains are largely out of contact with the aqueous solvent, and thus hydrophobic forces are an important determinant of protein structure, folding and stability. In proteins, the effects of hydrophobic forces are often termed hydrophobic bonding, to indicate the specific nature of protein folding under the influence of the hydrophobic effect. 

The hydrophobic effect refers to the favorable interactions between nonpolar surfaces immersed in water. These interactions are considered to provide the driving force for protein folding (44) and to make a major contribution to the stability of protein tertiary stractures. The hydrophobic effect also plays an important role in protein interactions (45). The hydrophobicity of protein surfaces has been studied experimentally by affinity partitioning of proteins (46). Theoretical studies have shown that the presence of hydrophobic patches on the surfaces of proteins correlates with protein binding sites (47 9). 

Discussion of the field of conformational analysis and protein folding is beyond the scope of this section. Nevertheless, the concept that the most potent drugs mimic the three-dimensional ( biologically active ) structure of the native peptide bound to its receptor became an important driving force in the field of peptide chemistry. The stabilization of this structure would result in increased potency and more efficacious pharmaceuticals. 

K. A. Dill, Dominant Forces in Protein Folding, Biochemistry, 29, (1990) 7133 K. A. Dill, Theory of the Folding and Stability of Globular Proteins, Biochemistry, 24 (1985) 1501. 

Hydrophobic interactions which are enforced (entropy driven) by the nature of water are the principle forces behind protein folding (6). They facilitate the establishment of other stabilizing interactions (7,10). Hydrophobic interactions, being of fundamental importance to protein structure, are very relevant to the functional properties of many food proteins, especially caseins. These forces affect solubility, gelation, coagulation, micelle formation, film formation, surfactant properties and flavor binding (7,10). 

Sharma, D., Perisic, O., Peng, Q., Cao, Y, Lam, C., Lu, H., and Li, H. 2007. Single-molecule force spectroscopy reveals a mechanically stable protein fold and the rational tuning of its mechanical stability, Proc Natl Acad Sci USA 104,9278-9283. 

Once the amino acids polymerize to form a polypeptide and ultimately folded in to a protein with specific conformation, the conformation of the entire polymer in the form of a functional protein is stabilized by combination of various internal and environmental forces and interactions. These interactive forces stabilize the polymer in the form of a functional protein. 

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