Protein Structure: Tertiary Bonds

Tertiary Structure Stabilizing Bonds

• Protein folding involves four key bonding interactions between side chains: covalent bonds, hydrophobic interactions, electrostatic interactions, and hydrogen bonding.
• Disulfide bonds are formed through the oxidation of thiol (-SH) groups on cysteine, crucial for protein stability, particularly in extracellular proteins.
• Ionic bonds form between oppositely charged amino acids, often located on the protein surface; interior ionic bonding is rare.
• Hydrogen bonding arises from interactions between N−H and C=O groups of peptide bonds, contributing to regular structures like α-helices and β-sheets.
• Hydrophobic interactions cause non-polar molecules to aggregate in aqueous solutions, forming a protective hydrophobic core within the protein.
• Long-range electrostatic interactions, such as salt bridges, provide significant stability, especially when buried in hydrophobic environments.
• London dispersion forces contribute medium-range weak attractions that enhance the stability of the protein's interior.

Primary Structure: The Peptide Bond

• A peptide bond (amide bond) forms by linking the α-carboxyl group of one amino acid to the α-amino group of another, releasing water and resulting from a condensation reaction.
• Polypeptides are chains of amino acids linked by peptide bonds, consisting of a repeating backbone and diverse side chains.
• Natural polypeptides typically comprise 50 to 2000 amino acid residues, with a defined directionality from the amino terminal to the carboxyl terminal.
• The backbone of polypeptides has hydrogen-bonding potential due to carbonyl groups and bonded hydrogen atoms from the amine group.
• Peptide bonds exhibit stability, with lifetimes of about 1000 years in the absence of catalysts, and are kinetically stable.
• The mass of proteins is measured in daltons, with 1 kDa equal to 1000 Da.

Properties of Peptide Bonds

• Peptide bonds possess partial double bond character, making them rigid and nearly planar, resulting in favored trans configuration due to a large dipole moment.
• The structure and properties of the protein are primarily dictated by the amino acid sequence, influencing the interactions within the polypeptide chain.
• Peptide bonds are less reactive compared to esters due to resonance, providing rigidity and inhibiting rotation.

Secondary Structure: α-helix and β-sheet

• Secondary structure is defined by the local spatial arrangement of the polypeptide backbone, shaped by hydrogen bonds between NH and CO groups of nearby amino acids.
• Prominent secondary structures include α-helices, β-sheets, and turns, while non-repetitive structures like loops and coils also form in some regions.
• The arrangement around the peptide bond and the identity of side chains are critical in determining the specific secondary structure of a protein.

Tertiary Structure Stabilizing Bonds

• Protein folding involves four key bonding interactions between side chains: covalent bonds, hydrophobic interactions, electrostatic interactions, and hydrogen bonding.
• Disulfide bonds are formed through the oxidation of thiol (-SH) groups on cysteine, crucial for protein stability, particularly in extracellular proteins.
• Ionic bonds form between oppositely charged amino acids, often located on the protein surface; interior ionic bonding is rare.
• Hydrogen bonding arises from interactions between N−H and C=O groups of peptide bonds, contributing to regular structures like α-helices and β-sheets.
• Hydrophobic interactions cause non-polar molecules to aggregate in aqueous solutions, forming a protective hydrophobic core within the protein.
• Long-range electrostatic interactions, such as salt bridges, provide significant stability, especially when buried in hydrophobic environments.
• London dispersion forces contribute medium-range weak attractions that enhance the stability of the protein's interior.

Primary Structure: The Peptide Bond

• A peptide bond (amide bond) forms by linking the α-carboxyl group of one amino acid to the α-amino group of another, releasing water and resulting from a condensation reaction.
• Polypeptides are chains of amino acids linked by peptide bonds, consisting of a repeating backbone and diverse side chains.
• Natural polypeptides typically comprise 50 to 2000 amino acid residues, with a defined directionality from the amino terminal to the carboxyl terminal.
• The backbone of polypeptides has hydrogen-bonding potential due to carbonyl groups and bonded hydrogen atoms from the amine group.
• Peptide bonds exhibit stability, with lifetimes of about 1000 years in the absence of catalysts, and are kinetically stable.
• The mass of proteins is measured in daltons, with 1 kDa equal to 1000 Da.

Properties of Peptide Bonds

• Peptide bonds possess partial double bond character, making them rigid and nearly planar, resulting in favored trans configuration due to a large dipole moment.
• The structure and properties of the protein are primarily dictated by the amino acid sequence, influencing the interactions within the polypeptide chain.
• Peptide bonds are less reactive compared to esters due to resonance, providing rigidity and inhibiting rotation.

Secondary Structure: α-helix and β-sheet

• Secondary structure is defined by the local spatial arrangement of the polypeptide backbone, shaped by hydrogen bonds between NH and CO groups of nearby amino acids.
• Prominent secondary structures include α-helices, β-sheets, and turns, while non-repetitive structures like loops and coils also form in some regions.
• The arrangement around the peptide bond and the identity of side chains are critical in determining the specific secondary structure of a protein.

Charged Amino Acids

• Arginine, histidine, lysine, aspartate, and glutamic acid are often surface-located, forming ion pairs and interacting with water.
• Charged side chains may bind inorganic ions like K+, PO4^3-, and Cl- to decrease repulsion.
• Charged amino acids in the protein interior typically create specific binding sites.

Polar Uncharged Amino Acids

• Serine, threonine, asparagine, glutamine, tyrosine, and tryptophan are usually found on the protein surface but can also form hydrogen bonds in the interior.

Functions of Globular Proteins

• Storage of Ions and Molecules: Myoglobin and ferritin.
• Transport of Ions and Molecules: Hemoglobin and serotonin transporter.
• Defense Against Pathogens: Antibodies and cytokines.
• Muscle Contraction: Actin and myosin.
• Biological Catalysis: Chymotrypsin and lysozyme.

Folds in Globular Proteins

• Folds refer to larger 3D structural patterns recognized as binding sites in proteins.
• Actin Fold: Involves ATP binding and hydrolysis first identified in G-actin, with four subdomains contributing to its structure.
• ATP binding induces a conformational change, leading to the cleavage of ATP to ADP.

Collagen Structure

• Collagen is characterized by a long, rigid triple helix formed by three polypeptides (α-chains).
• Collagen includes over twenty types and features the repeating polytripeptide sequence (–Gly–X–Y–), where X is usually proline and Y is hydroxyproline or hydroxylysine.
• Increased hydrogen bonding between chains contributes to structural strength.

Composition of Collagen

• Proline helps create kinks in the peptide chain, preventing it from forming typical α-helices.
• Glycine, the smallest amino acid, occupies every third position, facilitating the helix's compact structure.
• Collagen's surface exposure allows bonding between R-groups of adjacent collagen monomers, forming long fibers.

Hydroxyproline and Hydroxylysine

• Hydroxyproline and hydroxylysine, resulting from posttranslational modifications of proline and lysine, enhance collagen stability.
• Hydroxyproline maximizes interchain hydrogen bonds in the collagen structure.

Elastin Structure

• Elastin is a soluble protein polymer, with tropoelastin secreted into the extracellular space to interact with microfibrils like fibrilin.
• Rich in proline and lysine, elastin contains little hydroxyproline and no hydroxylysine.
• Elastin's unique properties include DESMOSINE cross-links, providing rubber-like elasticity.

Collagen-Related Diseases

• Osteogenesis Imperfecta (OI): Also known as brittle bone syndrome, characterized by fragile bones and potential kyphotic spinal deformity.
• Type II OI is lethal; severe cases often involve mutations in type I collagen genes.
• Mutations may replace glycine with bulkier residues, disrupting triple helix formation and structural integrity.

Explore the critical stabilizing bonds in protein tertiary structure through this quiz. Learn about the roles of covalent bonds, hydrophobic interactions, electrostatic interactions, and hydrogen bonding in maintaining protein stability. Test your understanding of how these interactions contribute to the overall 3D shape of proteins.