Folding of polypeptide chain

In this section, the structure, function, and reactivity of amino acids, peptides, and proteins will be discussed with the goal of providing a foundation for successful derivatization. The interplay of amino acid functionality and the three-dimensional folding of polypeptide chains will be seen as forming the basis for protein activity. Understanding how the attachment of foreign molecules can affect this tenuous relationship, and thus alter protein function, ultimately will create a rational approach to protein chemistry and modification. 

The folding of polypeptide chains and the assembly of multiple subunits are critical requirements when complex and multimeric proteins such as full size antibodies... 

These structures differ in the different hydrogen bond patterns that occur. Therefore, it is the hydrogen bond pattern that stabilizes folding of polypeptide chains. 

Clearly, the action of prolyl isomerases is not restricted to the slow folding of polypeptide chains with intact disulfides, but they also accelerate the oxidative folding of reduced proteins, which resemble more closely the nascent polypeptide chains as they occur in the endoplasmic reticulum. The simultaneous presence of PPI markedly enhances the efficiency of PDI as a catalyst of disulfide bond formation. Both enzymes act according to their specificity and catalyze the isomerization of prolyl peptide bonds and the formation of disulfide bonds, respectively, in the folding protein chains. It remains to be demonstrated that a similar concerted action of the two enzymes can take place in the course of de novo synthesis and folding of proteins in the cell. 

The generic tendency of proteins to aggregate into nonfunctional, and sometimes cytotoxic, structures poses a universal problem for all types of cells. This problem is exacerbated by the high total concentrations of macromolecules found within most intracellular compartments, but it is solved by the actions of certain proteins that function as molecular chaperones. Different chaperones act by distinct mechanisms on both the folding of polypeptide chains and their subsequent assembly into oligomeric structures. Many chaperones, but not all, are also stress (or heat shock) proteins because the need for a chaperone function increases under stress conditions that cause proteins to unfold. 

The folding of polypeptide chains into both helices (left) and sheets (right) involves amino acids that are fairly close together in the chain being held in position by hydrogen bonds. Other interactions among the various side chains are not shown here but play an important role in determining the three-dimensional shape of a polypeptide. 

The folding of polypeptide chains into ordered structures maintained by repetitive hydrogen bonding is called secondary structure. The chemical nature and structures of proteins were first described by Linus Pauling and Robert Corey who used both fundamental chemical principles and experimental observations to elucidate the secondary structures. The most common types of secondary structure are the right-handed cx-helix, parallel and antiparallel /3-pleated sheets, and (3-turns. The absence of repetitive hydrogen-bonded regions (sometimes erroneously called random coil ) may also be part of secondary structure. A protein may possess predominantly one kind of secondary structure (a-keratin of hair and fibroin of silk contain... 

The folding of polypeptide chain regions into regular structures defines die secondary structure of a protein. The tertiary folding between these regions involves both covalent disulfide bonds and non-covalent bonds. The quaternary structure exists in proteins that contain... 

The three-dimensional structure of the ternary complex of the dogfish enzyme with NAD and pyruvate is a separate and independent structure determination 136c). The two maps can be interpreted with the same overall fold of polypeptide chain and amino acid sequence. A list of a-car-bon coordinates and dihedral angles for both the apo- and ternary complex structures is given in Table V. 

Pis. 8.—The folding of polypeptide chains into a layer held together by imino-carbonyl hydrogen bonds. 

It seems not unlikely that the a-helix will be found to be the most generally prevalent mode of folding of polypeptide chains in proteins. 

Proteins are high molecular mass polypeptides with complex structures. The sequence of amino acids gives the primaiy structure of the protein, while the secondary and tertiary structures reveal the spatial properties of the peptide chain. The secrurdary structure takes into account the folding of polypeptide chains into domains called a-helices, jd-sheets, turns and coils, hr the ribbon representations of the protein structures illustrated in this chapter, the same colour coding is used to differentiate between... 

The polypeptide chains of all proteins are synthesized by the process described above. This mechanism gives rise to primary polypeptide chains, which are often further modified—for example, by cleavage into smaller peptides, by stmctural modification of selected amino acid residues, by splicing of the polypeptide chain, or by the formation of covalent bonds between polypeptide chains. Some of these secondary modifications are related to the correct folding of polypeptide chains and to the production of active enzymes or peptide hormones from inactive precursors (e.g., insulin from proinsulin). Also, the transport of proteins within the cell or the secretion of extracellular proteins is often linked to structural changes in polypeptide chains either during or after completion of synthesis. 

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