B1.2.7 Impact of primary structure on the conformation of proteins (HL) Notes

Primary Structure and Protein Folding

1. It acts as the blueprint for how the protein folds into its complex, three-dimensional conformation, ultimately determining its function.
2. Amino Acids and Peptide Bonds:
   1. Amino acids are joined by peptide bonds, forming a continuous chain.
   2. Each amino acid has a unique R-group (side chain) that interacts with others to influence folding.

From Linear to Three-Dimensional: The Hierarchy of Protein Folding

Proteins fold into complex shapes through a hierarchical process involving four levels of structure:

1. Primary Structure

1. Linear sequence of amino acids.
2. Foundation for all subsequent folding.

2. Secondary Structure

1. Regular patterns such as:
   1. Alpha-Helices: Spiral structures stabilized by hydrogen bonds between nearby amino acids.
   2. Beta-Pleated Sheets: Flattened, sheet-like structures formed by hydrogen bonds between more distant amino acids.
2. Stabilized by hydrogen bonds between backbone atoms, not R-groups.

3. Tertiary Structure:

1. Overall three-dimensional shape of a single polypeptide chain.
2. Maintained by interactions between R-groups, including:
   1. Hydrophobic interactions
   2. Hydrogen bonds
   3. Ionic bonds
   4. Disulfide bonds

4. Quaternary Structure:

1. Arrangement of multiple polypeptide chains (subunits) in a multi-subunit protein.

How the Primary Structure Dictates Protein Conformation

The sequence of amino acids in the primary structure is crucial for determining how a protein folds. Here's how:

1. Chemical Properties of R-Groups

1. Polarity, Charge, and Size:
   1. Hydrophobic R-Groups: Non-polar, tend to cluster away from water, forming the protein’s core.
   2. Polar and Charged R-Groups: Interact with water or other molecules, often located on the protein’s surface.

2. Order of Amino Acids

1. Sequence Specificity:
   1. The specific order of amino acids positions R-groups to form bonds or interactions.
   2. Predictable folding patterns arise from this sequence, guiding the protein to its functional shape.

3. Flexibility of the Backbone

1. Rotational Freedom:
   1. The polypeptide backbone can rotate around certain bonds, allowing flexibility in folding.
   2. Constraints are imposed by the chemical properties of R-groups, directing the folding process.

Why Protein Folding Is Predictable

1. Despite the complexity, protein folding is precise and repeatable due to several factors:
   1. Thermodynamic Stability: Proteins fold into the shape that minimizes their free energy, making this conformation the most stable.
   2. Chaperone Proteins: Helper proteins that assist in folding, ensuring proteins achieve their correct shapes.
   3. Evolutionary Design: Natural selection has optimized protein sequences for specific functions, ensuring reliable folding.

Implications of Protein Folding

1. Enzyme Activity: The active site’s shape is critical for binding substrates and catalyzing reactions.
2. Structural Proteins: Proteins like collagen depend on proper folding for mechanical strength.
3. Misfolding and Disease
   1. Misfolded proteins can aggregate and cause diseases, such as Alzheimer’s (amyloid plaques) or Parkinson’s (alpha-synuclein aggregates).
   2. Enzymes rely on their precise shape to form active sites that bind specific substrates.
4. Impact of Misfolding:
   1. Misfolded enzymes have altered or inactive active sites, preventing them from catalyzing reactions.