Chapter 6: The Three-Dimensional Structure of Proteins

The Three-Dimensional Structure of Proteins

1. Definition of Protein Structure Levels

  • Primary Structure (1°): Sequence of amino acids in a polypeptide chain.
  • Secondary Structure (2°): Local structures formed by hydrogen bonds, includes:
    • α-helix: Right-handed coil, 3.6 residues per turn, 1.5 Å rise per residue.
    • β-sheet: Stabilized by inter-strand hydrogen bonds, can be parallel or antiparallel; 2 residues per turn.
    • 310-helix: Right-handed helix with 3 residues per turn. Less common.
    • Polyproline II helix: Left-handed, prevalent in collagen, characterized by proline residues.
  • Tertiary Structure (3°): Overall 3D structure of a single protein molecule, determined by various interactions.
  • Quaternary Structure (4°): Assembly of multiple polypeptide chains (subunits), with symmetry types (e.g., homotypic, heterotypic).

2. Key Features of Secondary Structures

  • α-Helix:
    • Forms right-handed helix, side chains extend outward.
    • Hydrogen bonds form between i and i+4 residues.
  • β-Sheet:
    • Formed by two or more β-strands connected by hydrogen bonds.
    • Can be parallel (3.4 Å rise) or antiparallel (3.2 Å rise).
  • 310 Helix:
    • Right-handed, compact, not commonly found.
  • Polyproline II Helix:
    • Frequently observed, not stabilized by H-bonds; characteristic of collagen.

3. Pauling’s Rules for Secondary Structure

  1. Bond Angles/Lengths: Should be similar to free amino acids.
  2. Van der Waals Radii: No atoms should be closer than allowed.
  3. Amide Planarity: The amide group must remain planar.
  4. Stabilization: Non-covalent bonds (especially H-bonds) stabilize folding processes.

4. Ramachandran Plots

  • Usage: Maps allowed phi (ϕ) and psi (ψ) angles for amino acid residues.
  • Amino Acid Behavior:
    • Glycine has a higher number of allowed angles due to less steric hindrance compared to proline.

5. Thermodynamics of Protein Folding

  • Anfinsen’s Experiment: Demonstrated that primary sequence contains all information necessary for folding.
    • Involves denaturing and renaturing proteins under controlled conditions.
  • Stability Factors:
    • Salt bridges, hydrogen bonding, and van der Waals interactions all contribute to stability with negative enthalpy changes.
    • Folding involves a balance between enthalpy and entropy.

6. Protein Classification by Structure

  • Fibrous Proteins:
    • Elongated structures, used for structural support (e.g., collagen, keratin).
  • Globular Proteins:
    • Compact, complex structures, soluble in water, involved in diverse functions (e.g., enzymes).
  • Domains: Functional units within proteins, typically ~200 amino acids, can fold independently.

7. Quaternary Structure and Symmetry

  • Quaternary Structure: Formation of multi-subunit complexes, classified as:
    • Homotypic: Identical subunits.
    • Heterotypic: Different subunits.
  • Symmetry Types: C2, C3, and D2 symmetries relevant to structural classifications.

8. Protein Stability and Modification

  • Effects of Modifications:
    • Hydroxylation of proline enhances stability via hydrogen bonding.
    • Disulfide bonds contribute to stability but are less common in intracellular proteins.
  • Factors Influencing Stability:
    • Disulfide bond formation and binding of cofactors can also augment stability.

9. Dynamics of Protein Structure

  • Protein Folding Process:
    • Rapid folding, often within seconds; involves structured intermediate states.
    • Energy landscapes describe the folding pathways with respect to energetic stability.

10. Predicting Secondary and Tertiary Structures

  • Empirical Methods: Use amino acid distributions and patterns to predict secondary structures.
  • Computational Tools: Newer methods like AlphaFold enhance accuracy in tertiary structure prediction through advanced algorithms.

Conclusion

  • Understanding protein structure and dynamics is crucial for grasping biological functions and the implications in health and disease (e.g. amyloid fibrils and prions). This knowledge is foundational for advancements in biochemistry and molecular biology.