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Chapter 6: The Three-Dimensional Structure of Proteins

Four Levels of Protein Structure

Proteins exhibit a hierarchy of structural organization, each level contributing to the molecule's final shape and function.

• Primary Structure: The linear sequence of amino acids in a polypeptide chain, determined by the genetic code. This sequence dictates all higher levels of structure.

• Secondary Structure: Localized, repeating structures formed by hydrogen bonding between backbone atoms. The most common types are the α-helix and β-sheet.

• Tertiary Structure: The overall three-dimensional arrangement of all atoms in a single polypeptide chain, including interactions between secondary structure elements.

• Quaternary Structure: The spatial arrangement of multiple polypeptide chains (subunits) in a protein complex.

Example: Hemoglobin exhibits all four levels of structure, with four subunits assembling into a functional oxygen transport protein.

Common Secondary Structure Elements

Secondary structures are stabilized by hydrogen bonds and are critical for protein folding and stability.

• α-Helix: A right-handed coil where side chains radiate outward from the helix axis. Hydrogen bonds are nearly parallel to the helix axis. Often, α-helices have distinct hydrophilic and hydrophobic faces, contributing to protein folding and membrane association.

• β-Sheet: Composed of β-strands connected laterally by at least two or three backbone hydrogen bonds, forming a sheet-like structure. Side chains alternate above and below the plane of the sheet. β-sheets can be parallel (strands run in the same direction) or antiparallel (strands run in opposite directions).

Example: Silk fibroin is rich in β-sheets, providing strength and flexibility.

Table: Comparison of α-Helix and β-Sheet

Feature	α-Helix	β-Sheet
Hydrogen Bonding	Within a single chain, nearly parallel to helix axis	Between adjacent strands, perpendicular to strand direction
Side Chain Orientation	Radiate outward from helix	Alternate above and below sheet
Common Location	Transmembrane regions, globular proteins	Core of globular proteins, fibrous proteins

Fibrous Proteins: Structural Materials of Cells and Tissues

Fibrous proteins are elongated molecules with extensive secondary structure, providing mechanical support and strength to cells and tissues.

• Keratin: Found in hair, nails, feathers, and intermediate filaments. Characterized by a coiled-coil structure, where large hydrophobic residues repeat every four positions, creating a hydrophobic interface between helices.

• Fibroin: The main protein in silk, composed of close-packed β-sheets interrupted by compact folded regions, imparting both strength and some elasticity.

• Collagen: The most abundant connective tissue protein, forming a triple helix. Collagen fibers provide tensile strength to skin, bone, and cartilage.

Example: The coiled-coil structure of α-keratin is essential for the mechanical properties of hair and wool.

Globular Proteins: Tertiary Structure and Functional Diversity

Globular proteins are compact, generally water-soluble, and exhibit a wide range of functions due to their diverse tertiary structures.

• Contain varying amounts of α-helix, β-sheet, and loop regions.

• Larger proteins often consist of multiple domains, each a compact, independently folding unit (~200 amino acids) with a specific function (e.g., DNA binding, enzymatic activity).

Example: Human ubiquitin is a small globular protein involved in protein degradation, with a well-defined tertiary structure.

Factors Determining Secondary and Tertiary Structure

Protein folding and stability are governed by a balance of thermodynamic forces and chemical interactions.

• Favorable Intramolecular Enthalpic Interactions:

  • Charge-charge interactions (ionic bonds)

  • Intramolecular hydrogen bonds

  • Van der Waals interactions (dense packing of atoms)

• Unfavorable Loss of Conformational Entropy: The transition from an unfolded (high entropy) to a folded (low entropy) state is entropically unfavorable.

• Favorable Gain of Solvent Entropy (Hydrophobic Effect): Burying hydrophobic side chains in the protein interior releases ordered water molecules, increasing overall entropy.

• Disulfide Bonds: Covalent bonds between cysteine residues that greatly enhance protein stability, especially in extracellular proteins.

• Binding of Ions or Prosthetic Groups: Association with metal ions or cofactors can stabilize protein structure and are often essential for function.

Example: Disulfide bonds in bovine pancreatic trypsin inhibitor (BPTI) stabilize its tertiary structure.

Quaternary Structures—Symmetries

Many proteins function as multisubunit complexes, exhibiting specific symmetries that are important for their biological roles.

• Helical Symmetry: Seen in structures like actin filaments and the tobacco mosaic virus, allowing for indefinite growth in length.

• Point-Group Symmetry: Defined by the number and orientation of symmetry axes.

  • C2: One 2-fold axis (e.g., transthyretin dimer)

  • C3: One 3-fold axis

  • D2: Three 2-fold axes (e.g., phosphofructokinase tetramer)

  • D4: One 4-fold axis and two 2-fold axes

Example: The tetrameric enzyme phosphofructokinase displays D2 symmetry, which is important for its regulatory function in glycolysis.

Table: Types of Protein Symmetry

Symmetry Type	Description	Example
Helical	Repeating subunits along a helix	Actin filament
C2	One 2-fold axis	Transthyretin dimer
D2	Three 2-fold axes	Phosphofructokinase tetramer

Additional info: Protein structure is determined by both the sequence of amino acids and the physicochemical environment, including pH, temperature, and the presence of cofactors or chaperones.