KP

Biomolecule Structure Notes (Proteins, DNA, and RNA)

Protein Structure Levels

  • Polypeptides form proteins through a hierarchy of structures: primary, secondary, tertiary, and quaternary.
  • Primary structure: sequence of amino acids linked by peptide bonds.
  • Secondary structure arises from hydrogen bonding within the polypeptide backbone:
    • Alpha helices: a regular helix stabilized by hydrogen bonds between backbone atoms, specifically between the carbonyl oxygen of residue $i$ and the amide hydrogen of residue $i+4$; this i to i+4 pattern stabilizes the helicity. ext{H-bond: } ext{C=O}(i) \, \cdot\, \text{H-N}(i+4)
    • Beta pleated sheets: stabilized by inter-strand hydrogen bonds between segments; direction varies and a clear pattern is more evident for helices than for beta sheets.
  • Tertiary structure: three-dimensional folding of a single polypeptide chain.
    • Peptide bonds and backbone hydrogen bonds are still present.
    • Hydrophobic R groups (nonpolar amino acids) drive folding in aqueous environments because they prefer to avoid water (hydrophobic effect).
    • Polar solvents (like water) interact with polar R groups; nonpolar, hydrophobic R groups cluster together to stabilize the structure.
    • Ionic interactions (between charged R groups) further stabilize the fold.
    • Disulfide bonds (a special covalent bond) can form between cysteine residues (S–S bonds).
    • Note on sulfur chemistry: disulfide bridges contribute to protein stability; sulfur-containing compounds (e.g., in garlic) can involve disulfide-related chemistry and give characteristic odors; not all polypeptides have disulfide bonds, they are just one possible contributor to tertiary structure.
  • Quaternary structure: assembly of multiple polypeptide chains into a functional protein (protein subunits).
    • Many enzymes are multimeric with multiple subunits.
    • The concept clarifies that one gene can encode multi-subunit enzymes or multi-polypeptide complexes.

Examples of protein structures and implications

  • Collagen: the most abundant structural protein; provides a scaffold that maintains tissue firmness and integrity.
    • Functions as a structural framework in connective tissues; contributes to tissue strength and resilience.
  • Hemoglobin: a well-known multisubunit protein with subunits arranged as 2 alpha and 2 beta chains in adults.
    • Adult hemoglobin has $ ext{(α}2 ext{β}2)$ composition; fetal hemoglobin uses gamma ($ ext{γ}$) subunits instead of beta to adjust oxygen affinity.
    • Neonatal jaundice can relate to developmental switching of subunits (e.g., γ vs. β) and oxygen affinity dynamics.

Protein stability, denaturation, and regulation

  • Protein stability is influenced by the environment:
    • Salt concentration (ionic strength): differences inside vs outside the cell affect stability; cells regulate intracellular salt to prevent enzyme dysfunction.
    • Temperature: proteins denature when exposed to high temperatures.
    • A practical illustration: cooking an egg shows protein denaturation as the liquid becomes solid white.
    • In the human body, proteins begin denaturing at about T \,\approx\, 40^{\circ}\text{C} \ (\,104^{\circ}\text{F}); prolonged high fever (roughly t \gtrsim 4\text{–}5\ \text{hours}) can lead to widespread denaturation and cell death via apoptosis.
    • pH: extreme pH can denature proteins.
  • Chaperone proteins:
    • Promote proper protein folding inside the cytoplasm and, in some cases, outside the cell.
    • They help maintain proteins in the correct conformation when the environment (pH, ionic strength) would otherwise promote misfolding.
    • Misfolding is linked to neurodegenerative diseases (e.g., Alzheimer's disease with extracellular amyloid plaques and intracellular tangles; Parkinson’s disease with misfolded protein aggregates).
    • Prions: misfolded proteins that can induce misfolding in other proteins, leading to neurodegenerative disease; prions are not viruses or bacteria but aberrant proteins that disrupt folding.

Key notes on neurodegeneration and prions

  • Neurodegenerative diseases involve misfolded proteins and disrupted proteostasis:
    • Alzheimer's disease: amyloid plaques outside neurons; intracellular tangles of misfolded proteins.
    • Parkinson’s disease: protein misfolding and aggregation contribute to neuronal dysfunction.
    • Mad cow disease (prion disease): prions cause misfolding of normal proteins; cross-species transmission risk via contamination with neural tissue.
  • Prions can propagate by altering the folding pathway of normal proteins, leading to chain reactions of misfolding.

DNA structure and organization

  • DNA covalent backbone: phosphodiester bonds join nucleotides, forming the primary structure. The chain has directionality: 5' to 3' ends.
  • DNA secondary structure: base-pairing through hydrogen bonds forms the double helix.
    • Antiparallel orientation: the two strands run in opposite directions, giving 5' to 3' polarity on one strand opposite 3' to 5' on the other.
    • Base pairing rules (DNA): A\text{-}T: \text{2 hydrogen bonds}; \quad C\text{-}G: \text{3 hydrogen bonds}. (In RNA, A pairs with U, not T, but the transcript highlights A–T and C–G for illustrative purposes.)
  • Tertiary structure in DNA: beyond the classic double helix, DNA can form higher-order structures such as G-quadruplexes (G4).
    • G-quadruplexes involve stacks of guanine quartets stabilized by central cations (e.g., \mathrm{K}^+, \mathrm{Na}^+).
    • The central region often hosts ions that stabilize the quadruplex structure.
    • In the center of the quoted illustration, ions are shown as blue planes for visualization; they symbolize stabilizing cations rather than a direct chemical description.
  • Special DNA features related to regulation and aging:
    • Telomeres: ends of linear chromosomes; telomere length decreases with aging and genome stability changes.
    • Telomeres contain G-rich sequences that can form G-quadruplexes, which can influence gene regulation by stabilizing knot-like structures in promoter or telomeric regions.
    • G-quadruplexes in telomeres and promoter regions can regulate gene expression by restricting unwinding and transcription initiation until unwinding is accomplished.
  • Knots and genomic architecture:
    • In the context of chromosomal organization, certain knot-like structures (nuclear knots) can form to stabilize chromatin and regulate access to DNA.
    • Much of gene regulation begins with how DNA is bound to nucleosomes and higher-order structures; unwinding is required for transcription and expression.
  • Halliday/Holliday junctions (quaternary structure concept in genetics):
    • In 1964, Holliday proposed the Holliday junction model to describe a mechanism for genetic recombination and gene duplication during meiosis.
    • The idea of two double helices coming together to form a junction explains how genetic material can be copied and rearranged.

RNA structure and function

  • RNA is typically single-stranded in cells, making it less stable than DNA’s double helix.
  • Primary RNA structure: nucleotides linked by phosphodiester bonds (same chemistry as DNA for the backbone).
  • RNA secondary structure: stems (helical regions) and loops (unpaired regions) arising from intra-molecular base pairing.
  • Transfer RNA (tRNA) as a model:
    • tRNA folds into a characteristic cloverleaf secondary structure with stems and loops.
    • Three-dimensional (tertiary) conformation is further stabilized by unique features of its nitrogenous bases.
    • Bases and ring structures:
    • Nitrogenous bases are categorized into pyrimidines (six-membered rings) and purines (a fused five- and six-membered ring).
    • Canonical base-pairing in DNA (and RNA) involves hydrogen bonds; commonly cited is A–T (2 H-bonds) and C–G (3 H-bonds). In RNA, the equivalent is A–U pairing (2 H-bonds) and C–G (3 H-bonds). The transcript emphasizes A–T and C–G for teaching purposes, noting that in RNA the analogous pairing uses U instead of T.
    • Base pairing stability: regions rich in G–C pairs exhibit greater stability due to three hydrogen bonds vs. two in A–T (RNA: A–U) pairs.
  • RNA quaternary structure: the spliceosome
    • The spliceosome is a ribonucleoprotein complex that carries out pre-mRNA splicing.
    • It includes multiple RNAs (snRNA) and many protein subunits.
    • Example components cited: U2 snRNA and U6 snRNA (small nuclear RNAs); other snRNAs exist (and there are additional protein subunits) to form the functional spliceosome complex.
    • This quaternary assembly differs from protein-only quaternary structures, as RNAs themselves are integral components of the complex.

Summary of key concepts and connections

  • Structure determines function: sequence dictates folding patterns (secondary) and ultimately three-dimensional (tertiary/quaternary) assemblies that define biomolecule function.
  • Hydrophobic effects, hydrogen bonding, and ionic interactions collectively stabilize structures across proteins and nucleic acids.
  • Misfolding and aggregation are central to many diseases; chaperone systems protect against misfolding and assist in achieving correct folding.
  • DNA and RNA exhibit hierarchical organization and regulatory features that enable complex control of gene expression and genome stability; higher-order structures like G-quadruplexes and Holliday junctions reveal layers of regulation and recombination that extend beyond the canonical primary/secondary structure descriptions.
  • Practical implications include understanding how denaturation can disrupt cellular processes, how temperature and pH affect protein stability, and how multi-subunit assemblies (protein and ribonucleoprotein complexes) function in physiology and disease.