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 the final shape and function of the molecule.

• 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: Local regions of regular structure stabilized by hydrogen bonds, such as α-helices and β-sheets.

• Tertiary Structure: The overall three-dimensional arrangement of all atoms in a single polypeptide chain, including the spatial arrangement of secondary structural elements.

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

Example: Hemoglobin is a classic example of a protein with quaternary structure, consisting of four polypeptide subunits.

Common Secondary Structure Elements

Secondary structures are stabilized by hydrogen bonds and are fundamental to protein folding and function.

• α-Helix: A right-handed coil where side chains radiate outward from the helix axis. Hydrogen bonds are nearly parallel to the helix axis, and the helix often has 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. Side chains alternate above and below the plane of the sheet. Strands can be parallel (N→C in the same direction) or antiparallel (N→C 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 radiate away from the helical axis, and the core is tightly packed with backbone atoms. Hydrogen bonds stabilize the helix.

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

• Keratins: Found in hair, fingernails, feathers, scales, and intermediate filaments. Characterized by a coiled-coil structure with hydrophobic residues repeating every four positions, forming strong, stable fibers.

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

Example: Collagen's triple helix is stabilized by unique amino acids such as hydroxyproline and glycine.

6.3 Globular Proteins: Tertiary Structure and Functional Diversity

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

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

• Larger proteins often consist of two or more domains, which are independently folded regions, each with a specific function (e.g., DNA binding, oligomerization, cofactor binding).

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

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: The unfolded state has high entropy due to many possible conformations; folding reduces 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 interactions can further stabilize protein structure.

Equation:

$\Delta G = \Delta H - T\Delta S$

where $\Delta G$ is the change in free energy, $\Delta H$ is the change in enthalpy, $T$ is temperature, and $\Delta S$ is the change in entropy. Protein folding is favored when $\Delta G$ is negative.

Quaternary Structures—Symmetries

Quaternary structure refers to the arrangement and interaction of multiple polypeptide subunits in a protein complex. Many multisubunit proteins exhibit symmetry.

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

• Point-Group Symmetry: Includes various axes of 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

Symmetry Type	Example	Description
Helical	Actin, Tobacco Mosaic Virus	Capable of indefinite lengthening
$C_2$	Transthyretin Dimer	Twofold symmetry about a perpendicular axis
$D_2$	Phosphofructokinase Tetramer	Three 2-fold axes

Example: The tetrameric enzyme phosphofructokinase displays $D_2$ symmetry, important for its regulatory function in glycolysis.

Additional info: Domains are often evolutionary units, and their modularity allows for the evolution of new protein functions. Disulfide bonds are more common in extracellular proteins due to the oxidizing environment outside the cell.