Proteins are nature's molecular machines, built from amino acids and folded into intricate structures. From simple chains to complex 3D shapes, protein structure determines function. This hierarchy of organization is key to understanding how proteins work in our bodies.

Dive into the world of protein structure, where forces like hydrogen bonds and hydrophobic interactions shape these biological marvels. Learn about domains, motifs, and stability—essential concepts for grasping how proteins function and evolve in living systems.

Protein Structure Hierarchy

Levels of protein structure

• Primary structure
  • Linear sequence of amino acids determined by genetic code connected by peptide bonds forms backbone of protein
  • Sequence dictates folding and function (hemoglobin, insulin)
• Secondary structure
  • Regular, repeating patterns in polypeptide chain stabilize local regions
  • Alpha helices coil into right-handed spiral held by hydrogen bonds between backbone atoms (keratin)
  • Beta sheets form extended, pleated structure with hydrogen bonds between adjacent strands (silk fibroin)
  • Turns and loops connect other secondary structure elements allow flexibility (immunoglobulin domains)
• Tertiary structure
  • Three-dimensional arrangement of entire polypeptide chain formed by interactions between side chains
  • Determines overall shape and function of protein through folding into globular or fibrous structures (myoglobin)
• Quaternary structure
  • Arrangement of multiple polypeptide subunits in proteins with more than one chain
  • Subunits held together by non-covalent interactions create functional complexes (hemoglobin)

Forces in protein folding

• Hydrogen bonding
  • Forms between hydrogen atoms and electronegative atoms (O, N) stabilize secondary structures
  • Contributes to tertiary structure stability through intramolecular bonds (ribonuclease A)
• Disulfide bridges
  • Covalent bonds between cysteine residues provide strong structural support
  • Often found in extracellular proteins exposed to harsh environments (insulin)
• Hydrophobic interactions
  • Clustering of non-polar amino acid side chains drives formation of hydrophobic core in globular proteins
  • Contributes significantly to tertiary structure stability through exclusion of water (myoglobin)
• Van der Waals forces
  • Weak interactions between adjacent atoms contribute to overall protein stability
  • Important for protein-protein and protein-ligand interactions (enzyme-substrate binding)
• Ionic interactions
  • Electrostatic attractions between oppositely charged amino acid side chains
  • Stabilize tertiary and quaternary structures (salt bridges in thermophilic proteins)

Domains and motifs in proteins

• Protein domains
  • Distinct functional or structural units within protein that can fold independently
  • Often conserved across different proteins enabling modular architecture
  • Examples: DNA-binding domains (zinc finger), catalytic domains (kinase domain)
• Protein motifs
  • Specific combinations of secondary structure elements associated with particular functions
  • Allow prediction of protein function based on sequence or structure
  • Examples: leucine zipper (dimerization), helix-turn-helix (DNA binding)
• Significance
  • Facilitate protein evolution through domain shuffling creating new protein functions
  • Enable prediction of protein interactions and regulatory mechanisms (SH2 domains in signal transduction)
  • Guide protein engineering efforts for novel functions or improved stability

Structure-stability relationship in proteins

• Thermodynamic stability
  • Difference in free energy between folded and unfolded states typically ranges from 5-15 kcal/mol
  • Marginal stability allows for necessary flexibility in protein function
• Factors affecting stability
  1. Hydrophobic core formation excludes water and maximizes van der Waals interactions
  2. Hydrogen bonding networks throughout structure provide cooperative stability
  3. Electrostatic interactions between charged residues contribute to overall fold
  4. Conformational entropy opposes folding but is overcome by favorable interactions
• Protein denaturation
  • Disruption of native structure due to external factors (temperature, pH, chemical denaturants)
  • Reversible in some cases allowing refolding studies (ribonuclease A)
• Structure-stability relationships
  • Compact globular proteins generally more stable than extended structures due to increased intramolecular interactions
  • Thermophilic proteins often have additional stabilizing interactions (increased salt bridges)
  • Flexibility and stability trade-offs in protein function balance stability with necessary conformational changes
• Protein engineering
  • Rational design or directed evolution enhance stability for biotechnology applications
  • Techniques: site-directed mutagenesis, consensus design, ancestral sequence reconstruction
  • Applications: enzyme stability for industrial processes, therapeutic protein shelf-life extension