Proteins are the workhorses of cells, performing a vast array of functions. From enzymes that speed up chemical reactions to structural proteins that give cells shape, these molecular machines are essential for life. Their diverse roles stem from their unique structures, built from amino acid building blocks.

The relationship between protein structure and function is key to understanding how cells work. A protein's 3D shape, determined by its amino acid sequence, directly impacts its ability to perform specific tasks. This intricate connection between form and function is crucial for designing drugs, treating diseases, and advancing biotechnology.

Protein Building Blocks and Structure

Building blocks of proteins

• Amino acids are the fundamental units that make up proteins
  • 20 different amino acids commonly found in proteins each with unique properties
  • Amino acids consist of an amino group ($-NH_2$), carboxyl group ($-COOH$), hydrogen atom, and distinctive side chain (R group)
  • Side chain determines specific properties of each amino acid such as polarity (hydrophilic or hydrophobic), charge (positive, negative, or neutral), and size
• Amino acids classified based on side chain properties
  • Nonpolar (hydrophobic) amino acids have side chains that do not readily interact with water (Alanine, Valine, Leucine, Isoleucine, Proline, Phenylalanine, Tryptophan, Methionine)
  • Polar (hydrophilic) amino acids have side chains that interact with water through hydrogen bonding (Serine, Threonine, Cysteine, Asparagine, Glutamine)
  • Charged amino acids have side chains with positive (Lysine, Arginine) or negative (Aspartic acid, Glutamic acid) charges at physiological pH
  • Special cases include Glycine (simplest amino acid with hydrogen side chain), Histidine (positively charged or neutral depending on pH), and Tyrosine (aromatic and polar side chain)

Levels of protein structure

• Primary structure is the linear sequence of amino acids in a polypeptide chain
  • Determined by genetic code and amino acids linked by peptide bonds
  • Amino acid sequence is unique to each protein and crucial for proper folding and function
• Secondary structure is local folding of polypeptide chain into regular structures
  • $\alpha$-helix is coiled structure stabilized by hydrogen bonds between amino hydrogen and carboxyl oxygen atoms of amino acids four residues apart
  • $\beta$-sheet is structure formed by multiple polypeptide strands (parallel or antiparallel) stabilized by hydrogen bonds between strands
• Tertiary structure is three-dimensional folding of entire polypeptide chain
  • Stabilized by various interactions (hydrogen bonds, disulfide bridges, ionic interactions, hydrophobic interactions)
  • Determines overall shape and function of protein (active sites, binding pockets)
• Quaternary structure is arrangement of multiple polypeptide chains (subunits) into larger protein complex
  • Stabilized by same types of interactions as tertiary structure
  • Not all proteins have quaternary structure (monomeric vs multimeric proteins)

Peptide bonds in polypeptides

• Peptide bonds are covalent bonds linking amino acids to form polypeptide chains
  • Formed by condensation reaction between carboxyl group ($-COOH$) of one amino acid and amino group ($-NH_2$) of another, releasing water molecule
  • Peptide bond formation is endergonic and requires energy input (ATP hydrolysis)
• Peptide bonds have partial double bond character due to resonance
  • Restricts rotation around peptide bond, giving polypeptide chain rigid planar structure
  • Contributes to stability and shape of protein's secondary structure ($\alpha$-helices and $\beta$-sheets)
• Sequence of peptide bonds determines primary structure of protein
  • Directionality of polypeptide chain is from N-terminus (free amino group) to C-terminus (free carboxyl group)

Protein Function and Structure-Function Relationship

Functions of proteins

• Enzymes catalyze biochemical reactions by lowering activation energy
  • Specific to substrates and reactions (lock-and-key model, induced fit model)
  • Examples: DNA polymerase (DNA replication), pepsin (protein digestion), catalase (hydrogen peroxide decomposition)
• Hormones are chemical messengers that regulate physiological processes
  • Can be peptide hormones (insulin, growth hormone) or steroid hormones (estrogen, testosterone)
  • Bind to specific receptors on target cells to initiate signaling cascades
• Structural proteins provide support, protection, and movement in cells and tissues
  • Examples: collagen (connective tissue strength), actin and myosin (muscle contraction), keratin (hair and nail structure)
• Transport proteins move molecules across cell membranes or within body
  • Examples: hemoglobin (oxygen transport in blood), ion channels (membrane potential), glucose transporters (cellular glucose uptake)
• Signaling proteins are involved in cell communication and signal transduction
  • Examples: G protein-coupled receptors (hormones, neurotransmitters), protein kinases (phosphorylation cascades)
• Antibodies recognize and bind specific antigens as part of immune response
  • Produced by B lymphocytes and have variable regions for antigen binding
  • Different classes (IgG, IgM, IgA, IgE, IgD) with distinct functions
• Storage proteins store essential nutrients for later use
  • Examples: ferritin (iron storage in liver and spleen), casein (amino acid storage in milk), ovalbumin (amino acid storage in egg white)

Structure vs function in proteins

• Protein function is determined by its unique three-dimensional structure
  • Specific folding of polypeptide chain creates binding sites and active sites that enable protein to perform its function
  • Substrate specificity and catalytic activity of enzymes depend on precise arrangement of amino acids in active site
• Changes in protein structure can alter or disrupt protein function
  • Mutations in genetic code can change amino acid sequence (primary structure), affecting folding and stability of protein
  • Environmental factors (temperature, pH, denaturants) can disrupt interactions maintaining protein structure, leading to denaturation and loss of function
  • Misfolded or aggregated proteins can contribute to diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease)
• Post-translational modifications can regulate protein structure and function
  • Examples: phosphorylation (kinases and phosphatases), glycosylation (oligosaccharide attachment), acetylation (histone modification), methylation (DNA and protein modification)
  • Modifications can affect protein activity, localization, degradation, and interactions with other molecules
• Understanding structure-function relationship is crucial for:
  1. Designing drugs that target specific proteins involved in diseases
  2. Developing therapies for protein misfolding disorders
  3. Engineering proteins with novel or enhanced functions for biotechnology and synthetic biology applications