Proteins must achieve a specific three-dimensional shape, known as their conformation, to perform their biological functions. This final shape is built through a hierarchical process involving four levels of structure. Understanding protein folding requires knowing which forces contribute to the folding process and which interactions are characteristic of other structural levels, thus excluded from the definition of tertiary structure.
The Role of R-Groups in Defining Tertiary Structure
The tertiary structure represents the overall three-dimensional folding of a single, complete polypeptide chain. This organization is entirely determined by the interactions between the amino acid side chains, or R-groups. These interactions bring amino acids that may be far apart in the linear sequence into close proximity, creating the protein’s globular or fibrous form.
A key force driving tertiary folding is the hydrophobic interaction, where nonpolar R-groups cluster in the protein’s interior to minimize contact with the surrounding water environment. This exclusion of water is a major thermodynamic factor in protein stability.
The resulting structure is further stabilized by specific chemical interactions between R-groups. Ionic bonds, or salt bridges, form between oppositely charged R-groups (e.g., lysine and glutamate). Hydrogen bonds also occur between polar R-groups, helping to lock the folded structure into place. The strongest interaction is the disulfide bridge, a covalent bond between the sulfur atoms of two cysteine residues, which reinforces the protein’s shape.
Interactions Specific to Primary Structure
Interactions specific to the primary structure define the protein’s linear chain, not its three-dimensional folding. The defining interaction is the peptide bond. This is a strong, covalent amide linkage that joins the carboxyl group of one amino acid to the amino group of the next.
Peptide bonds form the rigid backbone of the polypeptide chain, establishing the sequence of amino acids from the N-terminus to the C-terminus. While this sequence is the blueprint for all higher-level structures, the peptide bond itself does not contribute to the final globular folding of the tertiary structure.
The rotation around the peptide bond is restricted due to its partial double-bond character, which influences how the chain can fold. However, the bond’s role is limited to connecting adjacent amino acids and does not involve the long-range interactions that characterize tertiary structure.
Interactions Specific to Secondary Structure
Secondary structure involves the local, repetitive folding of the polypeptide chain into patterns like the alpha-helix and the beta-pleated sheet. The interactions specific to this level, which are excluded from tertiary structure, are the hydrogen bonds between backbone atoms. These regularly repeating interactions occur between the carbonyl oxygen and the amide hydrogen atoms of the peptide backbone.
In an alpha-helix, the hydrogen bond forms between the carbonyl oxygen of one amino acid and the amide hydrogen four residues farther down the chain. In a beta-sheet, hydrogen bonds link the backbone atoms of adjacent strands.
The hydrogen bonds that define secondary structure are between uniform atoms in the peptide backbone. In contrast, the hydrogen bonds that contribute to tertiary structure occur between the variable R-groups, or between R-groups and the backbone, bringing distant regions of the chain together.
Interactions Specific to Quaternary Structure
The highest level of protein organization is the quaternary structure, which involves the assembly of multiple individual polypeptide chains, or subunits, into a single, functional protein complex. Interactions that occur between different polypeptide chains are excluded from the definition of tertiary structure, as tertiary structure is confined to a single chain.
The forces that stabilize quaternary structure are the same non-covalent interactions found in tertiary structure, including hydrophobic interactions, hydrogen bonds, and salt bridges. Here, however, they link one entire polypeptide subunit to another. For example, hemoglobin is composed of four separate subunits held together by these inter-chain interactions.
Disulfide bonds may also form between separate polypeptide chains, covalently linking the subunits. The formation of these inter-chain bonds is a specific feature of quaternary structure, differentiating it from the intra-chain folding that completes the tertiary structure. The purpose of quaternary structure is to create a multi-subunit complex that can perform more complex functions.