Tertiary structure of proteins

Mechanism of protein globule formation

The process of protein folding into a compact globule is driven by the chemical nature of amino acids. Structure formation proceeds in two main directions:

1. Formation of the hydrophobic core. Nonpolar (hydrophobic) amino acid side chains tend to avoid contact with water. They aggregate inside the molecule via hydrophobic interactions and van der Waals forces, forming a dense inner core.
2. Formation of the hydrophilic shell. Hydrophilic side chains, which can be either ionized or unionized, remain on the protein surface. It is this outer surface that contacts the environment and ensures good solubility of globular proteins in water.

Types of bonds in tertiary structure

The spatial shape is maintained through interactions between amino acid side chains. There are four main types of such bonds:

• Ionic bonds — electrostatic attraction between oppositely charged groups.
• Hydrogen bonds — formed between various uncharged hydrophilic groups.
• Hydrophobic interactions — association of nonpolar side chains within the globule.
• Disulfide bonds — strong covalent bridges formed upon oxidation and interaction of SH groups of two cysteine residues. They serve for additional stabilization of the structure of certain proteins.

Note: if hydrophilic residues happen to be hidden inside the hydrophobic core, they are still capable of interacting with each other, forming hydrogen or ionic bonds.

Conformational lability and homeostasis

Ionic, hydrogen, and hydrophobic interactions belong to the category of weak bonds. Their energy only slightly exceeds the energy of ordinary thermal motion of molecules. The final protein conformation is maintained due to a huge number of such weak contacts.

Atoms within the molecule are in constant motion. This leads to the continuous breaking of some weak bonds and the formation of new ones, causing local displacements of chain segments. The ability of a protein to slightly alter its shape is called conformational lability.

The working state of a molecule is called its native conformation. Under conditions of homeostasis (constancy of the internal environment), natural lability does not prevent the protein from performing its functions. However, if the internal environment changes abruptly—for example, due to sudden shifts in the concentration of protons, calcium ions, or glucose—the protein conformation is disrupted, leading to a loss of its functional activity.

Structural domains and their dynamics

Long polypeptide chains often do not form a single sphere, but fold into several separate compact regions — domains. Each domain possesses its own independent tertiary structure and resembles a separate small protein. The presence of domains significantly facilitates the process of correct folding of the entire complex molecule.

Domains are not static. When the active site of an enzyme binds to a ligand, domains can change their position. A classical example is the enzyme hexokinase, which catalyzes the transfer of a phosphate group from ATP to glucose. Its active site is located in the cleft between two domains. According to the "induced fit" mechanism, when hexokinase binds to a glucose molecule, the surrounding domains close tightly, securely locking the substrate in place to carry out the chemical reaction.

Classification of globular proteins

Depending on which secondary structures are present in the molecule, globular proteins are divided into four categories:

1. The first category includes proteins consisting exclusively of $\alpha$-helices. Clear examples are myoglobin and the $\beta$-chain of hemoglobin. A distinctive feature of these structures is the presence of exactly eight $\alpha$-helices in each molecule.
2. The second category combines proteins whose structure contains both $\alpha$-helices and $\beta$-structures. This group includes triosephosphate isomerase and the structurally similar domain of pyruvate kinase.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Structural features of the $\beta$-chain of hemoglobin and myoglobin
• Specificity of the enzymatic reaction of triosephosphate isomerase
• Effect of calcium ion concentration on protein conformation
• Differences between the remaining two categories of globular proteins
• Mechanism of glucose phosphorylation in the active site of hexokinase

Other topics in the section "Structure, Properties, and Functions of Proteins"

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