The theoretical number of different proteins is enormous. Since there are 20 different amino acids, there could be 20 x 20 = 400 distinct dipeptides (two linked amino acids), and 20 x 20 x 20 = 8,000 different tripeptides (three linked amino acids). Imagine this process of multiplying by 20 extended to a protein made up of 100 amino acids (which is considered a small protein). There could be 20100 such small proteins, each with its own distinctive primary structure. How large is the number 20100? There aren't that many electrons in the entire universe!

At the higher levels of protein structure, local coiling and folding give the molecule its final functional shape, but all of these levels derive from the primary structure—that is, the precise location of specific amino acids in the polypeptide chain. The properties associated with a precise sequence of amino acids determine how the protein can twist and fold, thus adopting a specific stable structure that distinguishes it from every other protein.

Primary structure is determined by covalent bonds. But the next level of protein structure is determined by weaker hydrogen bonds.

The secondary structure of a protein requires hydrogen bonding

A protein's secondary structure consists of regular, repeated patterns in different regions of a polypeptide chain. There are two basic types of secondary structure, both of them determined by hydrogen bonding between the amino acid residues that make up the primary structure.

the a helix. The a (alpha) helix is a right-handed coil that is "threaded" in the same direction as a standard wood screw (Figure 3.6b). The R groups extend outward from the peptide backbone of the helix. The coiling results from hydrogen bonds that form between the 8+ hydrogen of the N—H of one amino acid residue and the 8- oxygen of the C—O of another. When this pattern of hydrogen bonding is established repeatedly over a segment of the protein, it stabilizes the coil, resulting in an a helix. The presence of amino acids with large R groups that distort the coil or otherwise prevent the formation of the necessary hydrogen bonds will keep an a helix from forming.

The a-helical secondary structure is common in the fibrous structural proteins called keratins, which make up hair, hooves, and feathers. Hair can be stretched because stretching requires that only the hydrogen bonds of the a helix, not the covalent bonds, be broken; when the tension on the hair is released, both the hydrogen bonds and the helix re-form.

the b pleated sheet. A b (beta) pleated sheet is formed from two or more polypeptide chains that are almost completely extended and lying next to one another. The sheet is stabilized by hydrogen bonds between the N—H groups on one chain and the C— O groups on the other (Figure 3.6c). A P pleated sheet may form between separate poly-peptide chains, as in spider silk, or between different regions of the same polypeptide chain that is bent back on itself. Many proteins contain regions of both a helix and P pleated sheet in the same polypeptide chain.

The tertiary structure of a protein is formed by bending and folding

In many proteins, the polypeptide chain is bent at specific sites and then folded back and forth, resulting in the tertiary

Primary structure

Primary structure

Four Levels Protein Folding

Subunit 3

Subunit 4

Subunit 3

Subunit 4

3.6 The Four Levels of Protein Structure Secondary, tertiary, and quaternary structure all arise from the primary structure of the protein.

structure of the protein (Figure 3.6d). Although the a helices and P pleated sheets contribute to the tertiary structure, only parts of the macromolecule usually have these secondary structures, and large regions consist of structures unique to a particular protein.

While hydrogen bonding between the N—H and C = O groups within and between chains is responsible for secondary structure, the interactions between R groups—the amino acid side chains—determine tertiary structure. We described the various strong and weak interactions between atoms in Chapter 2 (see Table 2.1). Many of these interactions are involved in determining tertiary structure.

► Covalent disulfide bridges can form between specific cysteine residues (see Figure 3.4), holding a folded polypep-tide in place.

► Hydrophobic side chains can aggregate together in the interior of the protein, away from water, folding the polypep-tide in the process.

► van der Waals forces can stabilize the close interactions between the hydrophobic residues.

► Ionic bonds can form between positively and negatively charged side chains buried deep within a protein, away from water, forming a salt bridge.

A complete description of a protein's tertiary structure specifies the location of every atom in the molecule in three-dimen-

b Pleated sheet a Helix b Pleated sheet

A realistic depiction of lysozyme shows dense packing of its atoms.

A realistic depiction of lysozyme shows dense packing of its atoms.

The "backbone" of lysozyme consists of repeating C—C—N units of amino acids.

The "backbone" of lysozyme consists of repeating C—C—N units of amino acids.

3.7 Three Representations of Lysozyme Different molecular representations of a protein emphasize different aspects of its tertiary struc-ture.These three representations of lysozyme are similarly oriented.

sional space in relation to all the other atoms. Such a description is available for the protein lysozyme (Figure 3.7). The first tertiary structures to be determined took years to figure out, but today, dozens of new structures are published every week. The major advances making this possible have been the ability to produce large quantities of specific proteins by biotechnology and the use of computers to analyze the atomic data.

Bear in mind that both tertiary structure and secondary structure derive from a protein's primary structure. If lysozyme is heated slowly, the heat energy will disrupt only the weak interactions and cause only the tertiary structure to break down. But the protein will return to its normal tertiary structure when it cools, demonstrating that all the information needed to specify the unique shape of a protein is contained in its primary structure.

The quaternary structure of a protein consists of subunits

As mentioned earlier, many functional proteins contain two or more polypeptide chains, called subunits, each of them folded into its own unique tertiary structure. The protein's quaternary structure results from the ways in which these sub-units bind together and interact (see Figure 3.6e).

Quaternary structure is illustrated by hemoglobin (Figure 3.8). Hydrophobic interactions, van der Waals forces, hydrogen bonds, and ionic bonds all help hold the four subunits together to form the hemoglobin molecule. The function of hemoglobin is to carry oxygen in red blood cells. As hemoglobin binds one O2 molecule, the four subunits shift their relative positions slightly, changing the quaternary structure. Ionic bonds are broken, exposing buried side chains that enhance the binding of additional O2 molecules. The structure changes again when hemoglobin releases its O2 molecules to the cells of the body.

The surfaces of proteins have specific shapes

Small molecules in a solution are in constant motion. They vibrate, rotate, and move from place to place like corn in a a Subunits a Subunits

Four Subunits Hemoglobin

ß Subunits


ß Subunits


3.8 Quaternary Structure of a Protein Hemoglobin consists of four folded polypeptide subunits that assemble themselves into the quaternary structure shown here. In these two graphic representations, each type of subunit is a different color. The heme groups contain iron and are the oxygen-carrying sites.

a Helix popper. If two of them collide in the right circumstances, a chemical reaction can occur. The specific shapes of proteins allow them to bind noncovalently to other molecules, which in turn allows other important biological events to occur. Here are just a few examples:

► Two adjacent cells can stick together because proteins protruding from each of the cells interact with each other (see Chapter 5).

► A substance can enter a cell by binding to a carrier protein in the cell surface membrane (see Chapter 5).

► A chemical reaction can be speeded up when an enzyme protein binds to one of the reactants (see Chapter 6).

► A "multi-protein machine," DNA polymerase, can bind to and copy DNA (see Chapter 11).

► Another "multi-protein machine," RNA polymerase, can synthesize RNA (see Chapter 12).

► Chemical signals such as hormones can bind to proteins on a cell's outer surface (see Chapter 15).

► Defensive proteins called antibodies can recognize the shape of a virus coat and bind to it (see Chapter 18).

The biological specificity of protein function depends on two general properties of the protein: its shape and the chemistry of its exposed surface groups.

► Shape. When a molecule collides with and binds to a much larger protein, it is like a baseball being caught by a catcher's mitt: The mitt has a shape that binds to the ball and fits around it. A hockey puck or a ping-pong ball would not fit a baseball catcher's mitt. The binding of a molecule to a protein involves a general "fit" between two three-dimensional objects that becomes even more specific after initial binding.

► Chemistry. The surface of a protein has certain chemical groups that it presents to a substance attempting to bind to it (Figure 3.9). These groups are the R groups of the exposed amino acids, and are therefore a property of the protein's primary structure.

Look again at the structures of the 20 amino acids in Table 3.2, noting the properties of the R groups. Exposed hy-drophobic groups can bind to similarly nonpolar groups in the substance with which the protein interacts (often called the ligand). Charged R groups can bind to oppositely charged groups on the ligand. Polar R groups containing a hydroxyl (—OH) group can form a hydrogen bond with the ligand. These three types of interactions—hydrophobic, ionic, and hydrogen bonding—are weak by themselves, but strong when all of them act together. So the exposure of appropriate amino acid R groups on the protein surface allows the binding of a specific ligand to occur.

Knowing the exact shape of a protein and what can bind to it is important not only in understanding basic biology,

Ionic bonds occur between charged R groups on amino acids.

Hydrogen bonds form between two polar groups.

Hydrogen bonds form between two polar groups.

Two nonpolar groups interact hydrophobically.

3.9 Noncovalent Interactions between Proteins and Other Molecules Noncovalent interactions allow a protein to bind tightly to another molecule with specific properties, or allow regions within a protein to interact with one another.

but also in applied fields such as medicine. For example, the three-dimensional structure of a protease, a protein essential for the replication of HIV—the virus that causes AIDS—was first determined, then specific proteins were designed to bind to it and block its action. These protease inhibitors have prolonged the lives of countless people living with HIV (Figure 3.10).

Protein shapes are sensitive to the environment

Because it is determined by weak forces, protein shape is sensitive to environmental conditions that would not break co-valent bonds, but do upset the weaker noncovalent interactions that determine secondary and tertiary structure.

► Increases in temperature cause more rapid molecular movements and thus can break hydrogen bonds and hydrophobic interactions.

► Alterations in pH can change the pattern of ionization of carboxyl and amino groups in the R groups of amino acids, thus disrupting the pattern of ionic attractions and repulsions.

► High concentrations of polar substances such as urea can disrupt the hydrogen bonding that is crucial to protein

Lewis Bonding Model Hiv Drug

3.10 An HIV Protease Inhibitor After determining the structure of HIV protease (the blue polypeptide chain), a protein essential to the life cycle of HIV, biochemists designed a drug (the red space-filling model) to fit into the protease and block its function. Many people living with HIV and AIDS now take this drug.

structure. Nonpolar solvents may also disrupt normal protein structure.

The loss of a protein's normal three-dimensional structure is called denaturation, and it is always accompanied by a loss of the normal biological function of the protein (Figure 3.11).

Denaturing agents can disrupt the tertiary and secondary structure of a protein and destroy the protein's biological functions.

Denaturing agents can disrupt the tertiary and secondary structure of a protein and destroy the protein's biological functions.

Plasma Membrane Imaging
Renaturation (reassembly into a functional protein) is sometimes possible, but usually denaturation is irreversible.

3.11 Denaturation Is the Loss of Tertiary Protein Structure and Function Agents that can cause denaturation include high temperatures and certain chemicals.

Denaturation is often irreversible, because amino acids that were buried may now be exposed at the surface, and vice versa, causing a new structure to form or different molecules to bind to the protein. Boiling an egg denatures its proteins and is, as you know, not reversible. However, as we saw earlier in the case of lysozyme, denaturation may be reversible in the laboratory. If the protein is allowed to cool or the denaturing chemicals are removed, the protein may return to its "native" shape and normal function.

Chaperonins help shape proteins

There are two occasions when a polypeptide chain is in danger of binding the wrong ligand. First, following denatura-tion, hydrophobic R groups, previously on the inside of the protein away from water, become exposed on the surface. Since these groups can interact with similar groups on other molecules, the denatured proteins may aggregate and become insoluble, losing their function. Second, when a protein has just been made and has not yet folded completely, it can present a surface that binds the wrong molecule. In the cell, a protein can sometimes fold incorrectly as it is made. This can have serious consequences: In Alzheimer's disease, mis-folded proteins accumulate in the brain and bind to one anther, forming fibers in the areas of the brain that control memory, mood, and spatial awareness.

Living systems limit inappropriate protein interactions by making a class of proteins called, appropriately, chaper-onins (recall the chaperones—usually teachers—at school dances who try to prevent "inappropriate interactions" among the students). Chaperonins were first identified in fruit flies as "heat shock" proteins, which prevented denaturing proteins from clumping together when the flies' temperatures were raised.

Some chaperonins work by trapping proteins in danger of inappropriate binding inside a molecular "cage" (Figure 3.12). This cage is composed of several identical subunits, and is itself a good example of quaternary protein structure. Inside the cage, the targeted protein folds into the right shape, and then is released at the appropriate time and place.

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