Chapter 5.4

Proteins: Structure and Function

Introduction to Proteins

Proteins are essential macromolecules in all living organisms, responsible for a wide range of biological functions. Their specific activities are determined by their unique three-dimensional structures, which arise from the sequence of amino acids in their polypeptide chains.

• Proteins are polymers made up of amino acid monomers.

• Each protein has a unique structure that determines its function.

• Proteins can act as enzymes, structural components, signaling molecules, and more.

Amino Acids: The Building Blocks of Proteins

Structure of Amino Acids

Amino acids are organic molecules with a central carbon atom (the alpha carbon) bonded to four different groups: an amino group, a carboxyl group, a hydrogen atom, and a variable side chain (R group).

• Amino group ($-NH_2$)

• Carboxyl group ($-COOH$)

• Hydrogen atom

• Side chain (R group): Determines the unique properties of each amino acid

There are 20 standard amino acids, each with a different R group, which can be nonpolar, polar, acidic (negatively charged), or basic (positively charged).

Classification of Amino Acids by Side Chain Properties

Type	Examples	Properties
Nonpolar (hydrophobic)	Glycine, Alanine, Valine, Leucine, Isoleucine, Methionine, Phenylalanine, Tryptophan, Proline	Do not interact well with water
Polar (hydrophilic)	Serine, Threonine, Cysteine, Tyrosine, Asparagine, Glutamine	Form hydrogen bonds with water
Acidic (negatively charged)	Aspartic acid, Glutamic acid	Have carboxylate groups; negatively charged at physiological pH
Basic (positively charged)	Lysine, Arginine, Histidine	Have amino groups; positively charged at physiological pH

Polypeptides: Amino Acid Polymers

Formation of Polypeptides

Amino acids are linked together by peptide bonds (covalent bonds) to form polypeptides. A protein is one or more polypeptides folded into a specific three-dimensional structure.

• Peptide bond: Formed by a dehydration reaction between the carboxyl group of one amino acid and the amino group of another.

• Polypeptides can range from a few to over 1,000 amino acids in length.

• Each polypeptide has an N-terminus (amino end) and a C-terminus (carboxyl end).

Protein Structure

Levels of Protein Structure

The function of a protein is determined by its structure, which is organized into four hierarchical levels:

1. Primary structure: The unique sequence of amino acids in a polypeptide chain.

   • Determined by genetic information.

   • Like the order of letters in a word.

2. Secondary structure: Local folding of the polypeptide chain into structures such as alpha helices and beta pleated sheets.

   • Stabilized by hydrogen bonds between backbone atoms.

   • Common structures: Alpha helix and Beta pleated sheet.

3. Tertiary structure: The overall three-dimensional shape of a single polypeptide chain.

   • Results from interactions between R groups (side chains), including hydrogen bonds, ionic bonds, hydrophobic interactions, van der Waals forces, and disulfide bridges.

   • Disulfide bridges are strong covalent bonds that reinforce the protein's structure.

4. Quaternary structure: The association of two or more polypeptide chains into a functional protein complex.

   • Examples: Collagen (three polypeptides coiled together), Hemoglobin (four polypeptides: two alpha and two beta subunits).

Relationship Between Structure and Function

• The sequence of amino acids (primary structure) determines the three-dimensional structure of the protein.

• The structure of a protein determines its function.

• Protein function often depends on the ability to recognize and bind to other molecules (e.g., enzymes binding substrates, antibodies binding antigens).

Protein Models and Representations

Structural Models

Proteins can be represented using various models to illustrate their structure and function:

• Space-filling model: Shows the actual volume occupied by atoms.

• Ribbon model: Highlights the backbone and secondary structures (helices and sheets).

• Wireframe model: Emphasizes bonds and interactions, often used to show binding sites.

• Simplified diagrams: Used for general representations, such as enzyme-substrate interactions or cellular localization.

Protein Folding and Denaturation

Folding and Stability

Proteins fold into their functional shapes through a series of steps, guided by their primary structure. Proper folding is essential for biological activity.

• Physical and chemical conditions (pH, salt concentration, temperature) can affect protein folding.

• Denaturation: Loss of native structure due to environmental changes, resulting in loss of function.

• Denatured proteins are biologically inactive.

• Some denaturation is reversible if the denaturing agent is removed, but not always.

Protein Misfolding and Disease

• Misfolded proteins are associated with diseases such as Alzheimer's, Parkinson's, and mad cow disease.

• Cells have mechanisms (e.g., chaperone proteins like HSP70) to assist in proper folding and to respond to stress.

Example: Sickle Cell Disease

Sickle cell disease is an inherited blood disorder caused by a single amino acid substitution in the hemoglobin protein. This change alters the protein's structure and function, causing red blood cells to deform into a sickle shape and aggregate, leading to various health problems.

• Demonstrates how a small change in primary structure can have significant effects on protein function and organismal health.

Summary Table: Levels of Protein Structure

Level	Description	Stabilizing Forces	Example
Primary	Sequence of amino acids	Peptide bonds	Insulin chain
Secondary	Local folding (alpha helix, beta sheet)	Hydrogen bonds	Alpha helix in keratin
Tertiary	3D shape of polypeptide	Hydrogen bonds, ionic bonds, hydrophobic interactions, disulfide bridges	Myoglobin
Quaternary	Association of multiple polypeptides	Same as tertiary (between subunits)	Hemoglobin

Key Equations

• Peptide bond formation (dehydration reaction):

$\text{Amino acid}_1 + \text{Amino acid}_2 \rightarrow \text{Dipeptide} + H_2O$

• General formula for an amino acid:

$\mathrm{H_2N{-}CHR{-}COOH}$

Conclusion

Proteins are vital macromolecules whose structure at every level is crucial for their function. Understanding the relationship between amino acid sequence, protein folding, and biological activity is fundamental in biology and medicine.