The Three-Dimensional Structure of Proteins: Organization, Folding, and Function

Chapter 6: The Three-Dimensional Structure of Proteins

6.1 Secondary Structure: Regular Ways to Fold the Polypeptide Chain

The secondary structure of proteins refers to the local spatial arrangement of the polypeptide backbone, stabilized primarily by hydrogen bonding. The two most common secondary structures are the α-helix and β-pleated sheet.

• α-Helix: The carbonyl oxygen (C=O) of each peptide bond forms a hydrogen bond with the amide hydrogen (N–H) of the amino acid four residues ahead. This results in a right-handed helical structure.

• Stabilized by hydrogen bonds between backbone atoms of adjacent polypeptide chains (interchain) or within the same chain (intrachain). Strands can be parallel (both strands N→C) or antiparallel (one strand N→C, the other C→N). Side chains alternate above and below the plane of the sheet, giving rise to a zigzag structure.

• Peptide Bond Planarity: The partial double bond character of the peptide bond restricts rotation, fixing the atoms in the amide plane and limiting the possible secondary structures.

Example: Myoglobin consists almost entirely of α-helical secondary structure.

6.2 Fibrous Proteins: Structural Materials of Cells and Tissues

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

• Characteristics:

  • Polypeptide chains are organized parallel along a single axis.

  • Form long fibers or sheets, mechanically strong, and insoluble in water.

  • Play important structural roles (e.g., keratin in hair, collagen in connective tissue).

• Collagen Triple Helix:

  • Composed of three polypeptide chains wrapped around each other in a rope-like triple helix (tropocollagen, MW = 300,000).

  • Repeating sequence: X–Pro–Gly or X–Hyp–Gly (Hyp = hydroxyproline).

  • Every third position is glycine, allowing tight packing.

  • Stabilized by hydrogen bonds involving hydroxyproline and hydroxylysine; with age, cross-linked by covalent bonds (Lys and His).

Example: Collagen provides tensile strength to skin, bone, and connective tissue.

6.3 Globular Proteins: Tertiary Structure and Functional Diversity

Globular proteins fold into compact, roughly spherical shapes and perform diverse biological functions.

• Characteristics:

  • Backbone folds on itself; substantial sections of α-helix and β-sheet.

  • Polar side chains are exposed to the aqueous environment, interacting via hydrogen bonding and ion-dipole interactions.

  • Nonpolar side chains are buried in the hydrophobic core.

  • Soluble in water and salt solutions; compact structures.

• Example: Hemoglobin is a tetramer (α2β2) with homologous chains to myoglobin.

Comparison Table: Fibrous vs. Globular Proteins

Property	Fibrous Proteins	Globular Proteins
Shape	Elongated fibers/sheets	Compact, spherical
Solubility	Insoluble in water	Soluble in water
Function	Structural (e.g., collagen, keratin)	Functional (e.g., enzymes, hemoglobin)
Core	Hydrophobic surface	Hydrophobic interior, hydrophilic exterior

6.4 Factors Determining Secondary and Tertiary Structure

The folding and stability of protein structures are governed by several noncovalent interactions and covalent bonds.

• Hydrogen Bonding: Between backbone and polar side chains.

• Hydrophobic Interactions: Nonpolar side chains cluster in the protein interior.

• Electrostatic Interactions: Attraction between side chains of opposite charge.

• Metal Ion Coordination: Several side chains may complex with a single metal ion.

• Disulfide Bonds: Covalent bonds between cysteine side chains, restricting folding patterns.

6.7 Quaternary Structure of Proteins

Quaternary structure describes the spatial arrangement of multiple polypeptide chains (subunits) in a protein complex.

• Subunits: Each polypeptide chain in a multisubunit protein.

• Oligomers: Proteins made up of several subunits (dimers, trimers, tetramers).

• Interactions: Subunits interact noncovalently via electrostatic attractions, hydrogen bonds, and hydrophobic interactions.

• Allosteric Regulation: Conformational change in one subunit can induce changes in others, affecting protein function.

Protein Folding and Chaperones

Correct protein folding is essential for function. In the crowded cellular environment, proteins may misfold or aggregate.

• Chaperones: Specialized proteins (e.g., hsp70) that assist in proper folding and prevent aggregation.

• Example: α-hemoglobin stabilizing protein (AHSP) maintains the correct ratio of α- and β-chains in hemoglobin, preventing damage to blood cells.

Summary Table: Levels of Protein Structure

Level	Description
Primary	Amino acid sequence
Secondary	Local folding (α-helix, β-sheet)
Tertiary	3D arrangement of all atoms, including side chains
Quaternary	Assembly of multiple polypeptide chains

Key Points for Exam Preparation

• Understand the four levels of protein structure and their defining features.

• Be able to describe and compare α-helix and β-sheet structures, including hydrogen bonding patterns.

• Distinguish between fibrous and globular proteins in terms of structure, solubility, and function.

• Explain the role of noncovalent interactions and disulfide bonds in stabilizing tertiary and quaternary structures.

• Recognize the importance of chaperones in protein folding and the consequences of misfolding.