Box Extension 2.1 Protein Structure and the Bonds That Maintain It

All protein molecules have primary, secondary, and tertiary structure (and some have quaternary structure). Primary structure refers to the string of covalently bonded amino acids. As essential as primary structure is, protein function depends most directly on secondary and tertiary structure—the three-dimensional conformation of the protein molecule. Because secondary and tertiary structure are stabilized by weak chemical bonds rather than covalent bonds, the three-dimensional conformation of a protein can change and flex—a process essential for protein function. Denaturation is a disruption of the correct tertiary structure; because primary structure is not altered, denaturation may be reversible (reparable). Box Extension 2.1 presents detailed information on—and illustrations of—all levels of protein structure, strong versus weak bonds, the types of weak bonds, denaturation, and potential repair of denaturation.

Figure A The structural hierarchy of proteins

Any protein molecule consists of a linear series of amino acids, coded by a linear series of bases in the genetic material (DNA). The series of amino acids is termed the primary structure of the protein (Figure A1). The primary structure is important but is inadequate to account for the functional properties of proteins. Instead, each protein’s functional properties depend on the intricate three-dimensional shape, or conformation, of the protein molecule.

In analyzing the conformation of protein molecules, two increasingly complex levels of three-dimensional organization are recognized. The secondary structure of a protein molecule refers to subregions within the molecule in which the amino acids arrange themselves in highly regular geometric shapes; the two most common types of such highly ordered arrays are the α-helix and the β-sheet (pleated sheet) (Figure A2). The tertiary structure refers to the natural arrangement of an entire protein molecule in three dimensions, including its secondary structure and the other patterns of folding that give the molecule its particular conformation. Figure A3 shows two examples of tertiary structure. On the left is the three-dimensional structure of a subunit of the enzyme pyruvate kinase; it consists of several α-helices and β-sheets connected by strings of amino acids (the arrowheads on the sheets are merely artificial aids to help you trace the molecule from end to end). On the right is the three-dimensional structure of an O2-binding protein (myoglobin) that includes several α-helices in its structure; this protein is drawn as a tube that follows the natural contours of the molecule. Multiple formats are used to diagram tertiary structure (Figure B).

Figure B Three ways to diagram the tertiary structure of one protein All three diagrams represent lysozyme.

The primary structure of a protein is maintained by covalent bonds between successive amino acids in the amino acid chain. Covalent bonds depend on sharing of electrons between atoms. A relatively great amount of energy is required to break a covalent bond; thus covalent bonds are strong bonds.

The secondary and tertiary structures of a protein are maintained for the most part by noncovalent bonds that do not entail sharing of electrons. These sorts of bonds are weak bonds because they can be broken with relatively small amounts of energy. At least four mechanisms of noncovalent, weak bonding occur (Figure C).

Figure C Types of weak, noncovalent bonds that are important in protein structure The bonds are illustrated where they stabilize a hairpin fold in a protein molecule.

One is ionic bonding, which is electrostatic attraction between oppositely charged ionic regions of molecules. A second is hydrogen bonding, which occurs when a hydrogen atom covalently bonded to one atom (e.g., oxygen) is partially shared with another atom (e.g., another oxygen); for the most part, oxygen and nitrogen are the only sorts of atoms that associate by hydrogen bonding in biological systems. A third type of noncovalent bonding is van der Waals interaction, a type of attraction between nonpolar molecular regions that are close enough to each other to induce mutually attractive electric dipoles in each other’s electron fields or otherwise attract in a similar way. The fourth type of noncovalent bonding is hydrophobic bonding, the tendency of nonpolar regions to associate with each other within an aqueous solution because their close association is more thermodynamically stable than an alternative configuration that would permit water molecules in between. The secondary structure of a protein (e.g., a β-sheet) is maintained mainly by hydrogen bonds. The tertiary structure is maintained by all four sorts of weak bonds.

One of the most important properties of the tertiary structure of proteins is that it is flexible because of the weak bonding that maintains it; small changes in three-dimensional shape are often essential for proteins to function properly. The conformation of a protein cannot, however, deviate too far from its native state. We are all aware of the radical change that occurs in the albumin protein of a hen’s egg when we boil it; the protein changes from a transparent fluid to a white gel. As surprising as it may seem, the primary structure is not altered in this case. Instead, boiling corrupts the normal tertiary structure—an example of denaturation. Denaturation is a change in the three-dimensional structure of an intact protein that renders the protein nonfunctional. Cells have molecules called molecular chaperones that help ensure that a normal, functional three-dimensional conformation is maintained. Chaperones help guide proteins into their correct conformations during synthesis, and chaperones are sometimes able to guide reversibly denatured proteins back to their functional conformations, thereby preventing them from becoming permanently denatured.

Some proteins have quaternary structure (Figure A4). In such proteins, each finished molecule consists of two or more individual protein molecules bonded together into a multisubunit complex by weak (flexible) bonds. The quaternary structure refers to the three-dimensional arrangement of the subunit protein molecules in such an assembly. The example shown in Figure A4, which resembles mammalian hemoglobin, consists of four nearly identical molecules bound together in one assembly.