Tertiary and Quaternary Protein Structure - Amino Acids, Peptides, and Proteins - MCAT Biochemistry Review

MCAT Biochemistry Review

Chapter 1: Amino Acids, Peptides, and Proteins

1.5 Tertiary and Quaternary Protein Structure

Proteins can be broadly divided into fibrous proteins, such as collagen, that have structures that resemble sheets or long strands, and globular proteins, such as myoglobin, that tend to be spherical (that is, like a globe). These are caused by tertiary and quaternary protein structures, both of which are the result of protein folding.


A protein's tertiary structure is its three-dimensional shape. Tertiary structures are mostly determined by hydrophilic and hydrophobic interactions between R groups of amino acids. Hydrophobic residues prefer to be on the interior of proteins, which reduces their proximity to water. Hydrophilic N–H and C=O bonds found in the polypeptide chain get pulled in by these hydrophobic residues. These hydrophilic bonds can then form electrostatic interactions and hydrogen bonds that further stabilize the protein from the inside. As a result of these hydrophobic interactions, most of the amino acids on the surface of proteins have hydrophilic (polar or charged) R groups; highly hydrophobic R groups, such as phenylalanine, are almost never found on the surface of a protein.


The tertiary structure of a protein is primarily the result of moving hydrophobic amino acid side chains into the interior of the protein.

The three-dimensional structure can also be determined by hydrogen bonding, as well as acid–base interactions between amino acids with charged R groups, creating salt bridges. A particularly important component of tertiary structure is the presence of disulfide bonds, the bonds that form when two cysteine molecules become oxidized to form cystine, as shown in Figure 1.14. Disulfide bonds create loops in the protein chain. In addition, disulfide bonds determine how wavy or curly human hair is: the more disulfide bonds, the curlier it is. Note that forming a disulfide bond requires the loss of two protons and two electrons (oxidation).

Figure 1.14. Disulfide Bond Formation

The exact details of protein folding are beyond the scope of the MCAT, but the basic idea is that the secondary structures probably form first, and then hydrophobic interactions and hydrogen bonds cause the protein to “collapse” into its proper three-dimensional structure. Along the way, it adopts intermediate states known as molten globules. Protein folding is an extremely rapid process: from start to finish, it typically takes much less than a second.

If a protein loses its tertiary structure, a process commonly called denaturation, it loses its function.


Why do hydrophobic residues tend to occupy the interior of a protein, while hydrophilic residues tend to accumulate on the exterior portions? The answer can be summed up in one word: entropy.

Whenever a solute dissolves in a solvent, the nearby solvent molecules form a solvation layer around that solute. From an enthalpy standpoint, even hydrocarbons are more stable in aqueous solution than in organic ones (ΔH < 0). However, when a hydrophobic side chain, such as those in phenylalanine and leucine, is placed in aqueous solution, the water molecules in the solvation layer cannot form hydrogen bonds with the side chain. This forces the nearby water molecules to rearrange themselves into specific arrangements to maximize hydrogen bonding—which means a negative change in entropy, ΔS. Remember that negative changes in entropy represent increasing order (decreasing disorder) and thus are unfavorable. This entropy change makes the overall process nonspontaneous (ΔG > 0).


Make sure you understand the basic thermodynamic properties of enthalpy, entropy, and Gibbs free energy, discussed in Chapter 7 of MCAT General Chemistry Review. On Test Day, they can be tested on both natural sciences sections!

On the other hand, putting hydrophilic residues such as serine or lysine on the exterior of the protein allows the nearby water molecules more latitude in their positioning, thus increasing their entropy (ΔS > 0), and making the overall solvation process spontaneous. Thus, by moving hydrophobic residues away from water molecules and hydrophilic residues toward water molecules, a protein achieves maximum stability.


All proteins have elements of primary, secondary, and tertiary structure; not all proteins have quaternary structure. Quaternary structures only exist for proteins that contain more than one polypeptide chain. For these proteins, the quaternary structure is an aggregate of smaller globular peptides, or subunits, and represents the functional form of the protein. The classic examples of quaternary structure are hemoglobin and immunoglobulins, shown in Figures 1.15a and 1.15b. Hemoglobin consists of four distinct subunits, each of which can bind one molecule of oxygen. Similarly, immunoglobulin G (IgG) antibodies also contain a total of four subunits each.

Figure 1.15a. Hemoglobin α-subunits shown in red, β-subunits shown in blue. Heme molecules visible in each chain.

Figure 1.15b. Immunoglobulin G


The primary structure of a protein acts like letters. The secondary structure acts like words: only certain orderings of letters make sense (CAT is a word, while CAQ is not). The tertiary structure acts like sentences: words combine to form a functioning whole. The quaternary structure acts like paragraphs: they're not always present, but subunits can combine to make a cohesive whole.

The formation of quaternary structures can serve several roles. First, they can be more stable, by further reducing the surface area of the protein complex. Second, they can reduce the amount of DNA needed to encode the protein complex. Third, they can bring catalytic sites close together, allowing intermediates from one reaction to be directly shuttled to a second reaction. Finally, and most important, they can induce cooperativity, or allosteric effects. We'll discuss this much further in the next chapter (especially for hemoglobin), but the basic idea is that one subunit can undergo conformational or structural changes, which either enhance or reduce the activity of the other subunits.


The reduction of genetic material is crucial for viruses. The genome for most viruses is tiny. Thus, their viral coats typically consist of one small protein repeated dozens or even hundreds of times. Viral structure is discussed in Chapter 1 of MCAT Biology Review.


Conjugated proteins derive part of their function from covalently attached molecules called prosthetic groups. These prosthetic groups can be organic molecules, such as vitamins, or even metal ions, such as iron. Proteins with lipid, carbohydrate, and nucleic acid prosthetic groups are referred to as lipoproteins, glycoproteins, and nucleoproteins, respectively. These prosthetic groups have major roles in determining the function of their respective proteins. For example, each of hemoglobin's subunits (as well as myoglobin) contains a prosthetic group called heme. The heme group, which contains an iron atom in its core, binds to and carries oxygen; as such, hemoglobin is inactive without the heme group. These groups can also direct the protein to be delivered to a certain location, such as the cell membrane, nucleus, lysosome, or endoplasmic reticulum.

MCAT Concept Check 1.5:

Before you move on, assess your understanding of the material with these questions.

1. What are the definitions of tertiary and quaternary structure, and how do they differ in subtypes and the bonds that stabilize them?

Structural Element



Stabilizing Bonds

Tertiary structure (3°)

Quaternary structure (4°)

2. What is the primary motivation for hydrophobic residues in a polypeptide to move to the interior of the protein?