Chapter 6: The Three-Dimensional Structure of Proteins – Study Notes

Three-Dimensional Structure of Proteins

Four Levels of Protein Structure

The structure of proteins is organized into four hierarchical levels, each contributing to the protein's overall shape and function.

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

• Secondary Structure: Localized regions of repeating structure, primarily α-helix and β-sheet, stabilized by hydrogen bonds between backbone atoms.

• 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 multisubunit complex.

Example: Hemoglobin exhibits all four levels, with four polypeptide subunits forming a functional oxygen transport protein.

Common Secondary Structure Elements

Secondary structures are stabilized by hydrogen bonding 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 resulting in distinct hydrophilic and hydrophobic faces.

• β-Sheet: Composed of β-strands connected laterally by at least two or three backbone hydrogen bonds, forming a sheet-like structure. Strands can be parallel (same direction) or antiparallel (opposite direction).

Example: Silk fibroin is rich in β-sheets, contributing to its strength and flexibility.

Side Chain Positions in Secondary Structures

• In an α-helix, side chains radiate away from the helical axis, allowing for close packing of backbone atoms and stabilization by hydrogen bonds.

• In a β-sheet, neighboring side chains are located on opposite faces of the sheet, stabilized by hydrogen bonds between adjacent β-strands.

Fibrous Proteins: Structural Materials of Cells and Tissues

Characteristics and Examples of Fibrous Proteins

Fibrous proteins are elongated molecules with well-defined secondary structures, serving structural roles in cells and tissues.

• Keratin: Found in hair, fingernails, feathers, scales, and intermediate filaments. Characterized by a coiled-coil structure and repeating hydrophobic residues.

• Fibroin: The main protein in silk, composed of close-packed β-sheets interrupted by folded regions for elasticity.

• Collagen: The most abundant connective tissue protein, forming a triple helix and providing structural support in bone and other tissues.

Globular Proteins: Tertiary Structure and Functional Diversity

3D Representations and Domains

Globular proteins fold into compact, functional structures with diverse arrangements of helices, sheets, and loops.

• Proteins may contain multiple domains, each ~200 amino acids, folding independently and often associated with specific functions (e.g., DNA binding, oligomerization).

• Structural diversity is illustrated by proteins such as myoglobin, neuraminidase, and triosephosphate isomerase.

Factors Determining Secondary and Tertiary Structure

Thermodynamics, Folding, and Stability

Protein folding is governed by a balance of enthalpic and entropic factors, leading to stable, functional conformations.

• Favorable intramolecular enthalpic interactions:

  • Charge-charge interactions (ionic bonds)

  • Intramolecular hydrogen bonds

  • Van der Waals interactions (dense packing)

• Unfavorable loss of conformational entropy:

  • Unfolded state has high entropy (many conformations)

  • Folded state has low entropy (few conformations)

• Favorable gain of solvent entropy:

  • Burying hydrophobic groups releases ordered water molecules (hydrophobic effect)

• Disulfide bonds: Covalent bonds between cysteine residues greatly increase protein stability.

• Binding of ions or prosthetic groups: These interactions further stabilize protein structure.

Key Equations

• Gibbs Free Energy of Folding: $riangle G = riangle H - T riangle S$ Where $riangle G$ is the change in free energy, $riangle H$ is the change in enthalpy, $T$ is temperature, and $riangle S$ is the change in entropy.

Quaternary Structures—Symmetries

Types of Symmetry in Multisubunit Proteins

Quaternary structure involves the arrangement and symmetry of multiple polypeptide chains in a protein complex.

• Helical symmetry: Structures such as actin and tobacco mosaic virus can grow indefinitely in length.

• Point-group symmetry:

  • $C_2$: one 2-fold axis

  • $C_3$: one 3-fold axis

  • $D_2$: three 2-fold axes

  • $D_4$: one 4-fold axis and two 2-fold axes

• Examples:

  • Transthyretin dimer: $C_2$ symmetry (β-sandwich)

  • Phosphofructokinase tetramer: $D_2$ symmetry (three 2-fold axes)

Protein	Symmetry Type	Structural Feature
Actin	Helical	Indefinite length
Transthyretin	$C_2$	β-sandwich dimer
Phosphofructokinase	$D_2$	Tetramer, three 2-fold axes

Additional info: Symmetry in quaternary structure is crucial for the assembly and function of many protein complexes, influencing their stability and biological activity.