The Three-Dimensional Structure of Proteins (Chapter 6 Study Notes)

Chapter 6: The Three-Dimensional Structure of Proteins

Four Levels of Protein Structure

Proteins exhibit a hierarchy of structural organization, each level contributing to their final shape and function.

• Primary Structure: The linear sequence of amino acids in a polypeptide chain, held together by peptide bonds. This sequence determines 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, with four subunits (quaternary), each with its own tertiary structure, composed of helices (secondary), and a unique amino acid sequence (primary).

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, contributing to its strength and flexibility.

Side Chain Positions in Secondary Structures

• In an α-helix, side chains project outward from the helical backbone, minimizing steric hindrance and allowing for interactions with the environment.

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

6.2 Fibrous Proteins: Structural Materials of Cells and Tissues

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

• Keratin: Found in hair, fingernails, feathers, scales, and intermediate filaments. It forms a coiled-coil structure, with large hydrophobic residues repeating every four positions, creating a hydrophobic interface between helices.

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

• Collagen: The most abundant connective tissue protein, forming a triple helix. Collagen fibers provide tensile strength to tissues and serve as a matrix for bone mineralization.

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

6.3 Globular Proteins: Tertiary Structure and Functional Diversity

Globular proteins are compact, generally spherical proteins with diverse functions and complex tertiary structures.

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

• Larger globular proteins often consist of two or more domains, which are independently folded regions (~200 amino acids) that often have specific functions (e.g., DNA binding, enzymatic activity).

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

Representations of 3D Structures

• Cartoon models show the arrangement of secondary structure elements.

• Stick models display atomic details, including hydrogen bonds.

• Surface models illustrate the solvent-accessible surface and charge distribution.

6.4 Factors Determining Secondary and Tertiary Structure

The folding and stability of proteins are governed by thermodynamic principles and various molecular 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: Folding reduces the number of possible conformations, decreasing entropy.

• 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 increase protein stability.

• Binding of ions or prosthetic groups: These can stabilize protein structure and are often essential for function (e.g., heme in hemoglobin).

Equation:

• Protein folding is driven by the change in Gibbs free energy ($\Delta G$): $\Delta G = \Delta H - T\Delta S$ where $\Delta H$ is the change in enthalpy, $T$ is temperature, and $\Delta S$ is the change in entropy.

Quaternary Structures—Symmetries

Many proteins function as multisubunit complexes, exhibiting specific symmetries in their quaternary structure.

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

• Point-group symmetries: Defined by the number and orientation of symmetry axes.

  • $C_2$: 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

Example Table: Common Symmetries in Protein Complexes

Symmetry Type	Description	Example
Helical	Repeating subunits along a helix	Actin filament
$C_2$	Twofold rotational symmetry	Transthyretin dimer
$D_2$	Three perpendicular 2-fold axes	Phosphofructokinase tetramer

Additional info: Domains are often evolutionarily conserved and can be recombined in different proteins to create new functions. Disulfide bonds are more common in extracellular proteins, where the environment is more oxidizing.