Protein Structure: Levels and Importance

Importance of Protein Structure

• Structure dictates function: Understanding structure is key to understanding protein function.
• Purpose: Proteins bind ligands, transport, scaffold, catalyze (enzymes), regulate gene expression, and act as hormones.
• Misfolding: Incorrect folding leads to disease states as proteins cannot perform intended functions.

Levels of Protein Structure

I. Primary Structure

• Definition: Covalently bound amino acid residues forming a specific sequence.
• Peptide Bonds: Formed by amino acid condensation; possess partial double bond character due to resonance, making them planar.
• Rotation: Occurs only around $N-C\alpha$ ($\phi$) and $C(O)-C\alpha$ ($\psi$) bonds; limited by steric hindrance.

II. Secondary Structure

• Definition: Localized folding patterns formed by repetitive hydrogen bonds within the peptide backbone.
• Formation: Driven by rotations about $\phi$ and $\psi$ angles.

A. \alpha-helix

• Structure: Helical, stabilized by hydrogen bonds between the peptide $C=O$ of residue $n$ and $N-H$ of residue $(n+4)$.
• Characteristics:
  • Residues per turn: $3.6$
  • Rise per residue: $1.5$ \unicode{x212B}
  • Pitch (rise per turn): $5.4$ \unicode{x212B}
• Side Chains: Extend away from the helical axis.

B. \beta-sheet

• Structure: Extended conformation with hydrogen bonds forming between backbone atoms of different stretches of the same polypeptide or different chains.
• Orientation: Can be parallel or antiparallel; antiparallel is more stable due to $180 \degree$ alignment of donors/acceptors.
• Side Chains: Best accommodates small, uncharged side chains.
• Turns: Required for sheet formation; simple turns (antiparallel) and crossover turns (parallel).

C. \beta-turns (or \beta-bends, reverse turns)

• Function: Polypeptide reverses direction, folding back on itself.
• Key Residues: Proline (rigidity) and Glycine (small side chain for tight packing).
• Stabilization: Hydrogen bonds between carbonyl O of one residue and amide H of a residue three residues away.

III. Supersecondary Structures (Motifs)

• Definition: Clusters of secondary structures within the same peptide chain.
• Function: Not always correlated to a particular function.
• Examples:
  • $\beta\alpha\beta$: Two parallel $\beta$-strands connected by an $\alpha$-helix.
  • $\beta$-hairpins: Antiparallel sheet formed by tight reverse turns.
  • $\alpha\alpha$: Two antiparallel $\alpha$-helices.
  • Greek Key motif: Repetitive antiparallel sheet folding back on itself.

IV. Domains

• Definition: Larger, stable clusters of secondary structures that fold independently and fulfill a specific function.
• Connection: Linked to other domains by a linker region within the same polypeptide.
• Function Correlation: Similar domains often indicate similar protein functions.

V. Tertiary Structure

• Definition: The overall three-dimensional folded structure of a single polypeptide chain.
• Interactions: Involves interactions between side chains and between side chains and backbone atoms.
  • Non-covalent: Hydrophobic interactions (hydrophobic core), ionic bonds, hydrogen bonds.
  • Covalent: Disulfide bonds (more common in harsher, oxidizing extracellular environments).
• Non-amino Acid Components: Can include prosthetic groups (e.g., heme, NAD$\text{+}$) and metal ions (e.g., Ni, Zn, Co, Fe) for structure or catalysis.

VI. Quaternary Structure

• Definition: Applies to proteins with multiple subunits; describes the interactions between these subunits.
• Interactions: Similar types of interactions as in tertiary structure (non-covalent and disulfide bonds) stabilize subunit interfaces.