protein structure

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Biomolecules and Metabolism BCH1003 Lecture 2: Proteins Structure

  • Presented by: Assistant Professor Keith Rochfort

  • Date: 11th September 2025

Overview of Protein Structure

  • The function of a protein is strictly connected to its structure.

  • Proteins contain up to four levels of structure:

    • Primary: The basic amino acid sequence of the protein.

    • Quaternary: The most complex arrangement, observed only in some proteins.

  • The destruction of proteins can occur if intermolecular forces are disrupted.

Effects on Protein Structure

  • Heating:

    • Breaks hydrogen bonds.

  • Changing pH:

    • Can either protonate or deprotonate amino acid residues, thus interrupting ionic interactions.

  • Reducing Agents:

    • Can break disulfide linkages.

Primary Structure of Proteins

  • Definition: The sequence of amino acids in a protein.

  • All proteins have a primary structure as they consist of amino acid sequences.

  • This structure serves as the foundation for the higher levels of protein structure.

Primary Structure Formation

  • The synthesis of a protein involves:

    1. tRNA transfers specific amino acids to the ribosome.

    2. Amino acids connect through the formation of peptide bonds:

    • Dipeptide: Formed when two amino acids join via the first peptide bond.

    • Tripeptide: Formed from three amino acids joining via subsequent peptide bonds.

    1. This process continues to create longer chains known as polypeptides, constituting proteins.

Structural Ends of Polypeptides

  • N-terminal: The end with the amino group.

  • C-terminal: The end with the carboxylate group.

  • Backbone Properties: Consistent throughout, while the variations lie in side chains (R groups).

  • The backbone has numerous sites for potential hydrogen bond formation due to:

    • Each amino acid carrying an -NH group (acting as hydrogen bond donors).

    • Each carrying a carbonyl (C=O) group (acting as hydrogen bond acceptors).

Historical Context

  • The primary structure of proteins like bovine insulin was the first to be characterized, leading to over 100,000 proteins identified since then.

Secondary Structure

  • Composed of local folding of polypeptide chains into structures stabilized by hydrogen bonds.

  • Key types include:

    • α-Helix: Twists into a spring-like structure.

    • β-Pleated Sheets: Composed of extended strands.

α-Helix Details

  • Characteristics:

    • Tightly wound spring structure.

    • The backbone forms the core; side chains extend outward.

    • Each turn consists of 3.6 amino acids, where:

    • One hydrogen bond forms between the -CO of one amino acid and the -NH of one four-residue-apart amino acid.

  • Helices are predominantly right-handed due to energetic favorability.

β-Pleated Sheets

  • Formed by linking multiple strands through hydrogen bonds.

  • Strands can align in:

    • Parallel β-sheet: Adjacent strands run in the same direction (N-terminal to C-terminal).

    • Anti-parallel β-sheet: Adjacent strands run in opposite directions.

  • Side chains of adjacent amino acids point in differing directions in β-sheets.

  • Typical sheets consist of 4-10 strands and can be fully parallel, fully anti-parallel, or mixed.

Turns and Loops

  • Proteins often require compact shapes, using:

    • Reverse turns: Bonding between the -CO and -NH groups three amino acids apart.

    • Loops (Ω loops): More complex and randomly arranged structures that lack periodicity but form rigid shapes on protein surfaces.

Tertiary Structure

  • The final 3D configuration of a protein affected by:

    • Interactions between side chains.

    • Arrangement of hydrophobic and polar side chains plays a significant role:

    • Nonpolar side chains aggregate in the protein’s interior.

    • Polar side chains remain exposed on the surface due to hydrophobic interactions.

Tertiary Structure Formation

  • Integrates various forces:

    • Van der Waals interactions: Between closely packed side chains.

    • Ionic interactions: Between charged side chains.

    • Disulfide bridges: Formed between cysteine residues.

Specific Folding Patterns in Tertiary Structures

  1. Four-Helix Bundle Fold: Four α-helices linked via hydrophobic interactions, providing stability and adaptability.

  2. Greek Fold: Beta-sheet motif resembling a traditional pattern; stabilized via hydrogen bonds.

  3. FERM Domain Fold: Cloverleaf-like configuration, highly conserved, interacts with plasma membrane.

  4. TIM Barrel Fold: Alternating α-helices and β-strands forming a stable structure surrounding a β-barrel.

  5. Rossmann Fold: Consists of alternating α-helices and β-strands; typical in nucleotide-binding proteins.

Quaternary Structure

  • Involves interactions between multiple polypeptide chains called subunits.

  • Dimer: The simplest form, consisting of two identical subunits.

Complex Quaternary Structures

  • Common in proteins with different subunits:

    • Example: Hemoglobin with two pairs of globin subunits.

  • Viral coats demonstrate more intricate structures comprising various subunits.

Protein Misfolding Disorders

  • Proper folding is critical for function and involves chaperones to prevent misfolding.

  • Misfolded proteins may:

    • Lose original function or gain harmful properties, leading to conditions such as:

    • Alzheimer's Disease: Characterized by β-amyloid and tau aggregation.

    • Parkinson's Disease: Due to α-synuclein aggregates.

    • Huntington's Disease: Resulting from expanded polyglutamine sequences in huntingtin.

    • Cystic Fibrosis: Result of CFTR misfolding, affecting chloride transport.

Importance of Understanding Protein Folding

  • Enhances therapeutic design and accuracy in diagnosing diseases related to protein structure abnormalities. Correct folding is paramount for protein functionality and stability.