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Flashcards in this deck (24)
  • The four levels of protein structure are: - Primary: linear sequence of amino acids - Secondary: folding into alpha helices and beta sheets via hydrogen bonds - Tertiary: 3D folding via hydrophobic interactions, salt bridges, disulfide bonds - Quaternary: multi-subunit complexes via non-covalent interactions

  • B-DNA characteristics: - Right-handed common form following Watson-Crick geometry - Bases perpendicular to axis - 10 bases per turn - 34 Å per turn (3.4 Å between bases)

  • A-DNA characteristics: - Right-handed but more twisted and compact - Found in DNA:RNA hybrids and during transcription - Bases tilted ≈20° from axis - 11 bases per turn and 28 Å per turn (~2.5 Å between bases)

  • Z-DNA characteristics: - Transient and less stable than A or B - Seen in DNA with G-C repeats and recognized by RNA editing enzymes - Bases tilted 9° from axis - 12 bp per turn and 45 Å per turn (~3.8 Å between bases)

  • A DNA melting curve monitors DNA denaturation vs temperature. The melting temperature (Tm) is the temperature where 50% of DNA is denatured, and a higher Tm indicates higher G-C content.

  • A Cot curve studies DNA reassociation complexity using Cot = \(Co \times t\) (Concentration × time). Highly repetitive sequences reassociate early and quickly, while more complex sequences reassociate later.

  • Genomic imprinting is present in mammals and angiosperms and requires both parental genomes for normal development; it involves DNA methylation of cytosines adjacent to guanines and differential methylation during oogenesis and spermatogenesis.

  • Evidence from mouse experiments: embryos with two egg nuclei (gynogenotes) failed midterm development, while embryos with two sperm nuclei (androgenotes) formed placental membranes but no embryo, showing both parental imprints are necessary.

  • Plasmid DNA runs as two bands on agarose gel because plasmids exist as open circular (relaxed) and supercoiled forms that migrate at different rates despite identical sequence.

  • Basic plasmid isolation workflow: - Pellet cells by centrifugation and resuspend in mild buffer - Add NaOH + SDS to denature DNA and lyse cells - Neutralize with acetic acid to precipitate chromosomal DNA, proteins, lipids - Plasmid reanneals and remains in supernatant for silica column purification

  • After column washing, RNase is added to remove RNA, leaving a pure plasmid sample. Results are checked with gel electrophoresis.

  • Transformation is the addition of foreign DNA (usually a plasmid) into a bacterium.

  • To make E. coli competent in the lab, cells are treated with CaCl2 on ice because calcium acts as a bridge between negatively charged cell membrane and negatively charged DNA, attracting plasmid to the cell surface.

  • Cells are grown to mid log phase (A600 = 0.4-0.6) before transformation because adhesion zones (protein channels used for DNA uptake) are most common at this stage.

  • After plasmid-coated cells are heat shocked to activate DNA uptake, they are recovered by adding LB broth and incubating at 37 C for 45 mins before plating on LB/ampicillin.

  • Ampicillin-resistance gene (AmpR) on a plasmid acts as a selectable marker so that after plating on LB/ampicillin, only transformed cells carrying AmpR will grow.

  • Cell density of a culture can be determined by plating bacteria on solid LB/agar and counting colonies, since each colony arises from a single cell (a clone).

  • E. coli reaches approximately 10^9 cells/mL during stationary phase.

  • Basic features of E. coli: rod shaped, gram negative (double membrane), enteric bacterium that lives in the GI tract, optimal growth at 37 C.

  • E. coli genetic & growth details: large circular chromosome (~3E6 bp), can carry multiple small circular plasmids, divides every 22 mins, and grows in LB (liquid) and LB + agar (solid).

  • Restriction enzymes are DNases that cut DNA at specific palindromic restriction sites (usually 4 or 6 bp), serving bacterial defense against bacteriophages.

  • EcoR1 makes a staggered cut with a 5' overhang, and a 5' overhang produces sticky ends.

  • Features of R-plasmids: high copy number (10-500 copies per cell), they are relatively small and typically carry antibiotic resistance genes.

  • All plasmids require an origin of replication (oriR) and depend on cytoplasmic proteins such as DNA polymerase for replication; bacteria retain R-plasmids because the antibiotic resistance provides a selective advantage.

Study Notes

Protein structure

  • Primary structure: linear amino acid sequence of a polypeptide.
  • Secondary structure: local folding stabilized by hydrogen bonds into alpha helices and beta pleated sheets.
  • Tertiary structure: overall 3D fold stabilized by hydrophobic interactions, salt bridges, hydrogen bonds, and disulfide bonds.
  • Quaternary structure: assembly of multiple polypeptide subunits via noncovalent interactions.

DNA conformations: A, B and Z

  • B-DNA — the canonical form: right-handed; bases roughly perpendicular to the helix axis; \(10\\ \\\text{bp/turn}\); \(34\\ \\\text{\\AA}/\\text{turn}\) so \(3.4\\ \\\text{\\AA}\) between bases.
  • A-DNA — right-handed, more compact; bases tilted ~20°; \(11\\ \\\text{bp/turn}\); \(28\\ \\\text{\\AA}/\\text{turn}\) so ~\(2.5\\ \\\text{\\AA}\) between bases; common in DNA:RNA hybrids and some transcriptional states.
  • Z-DNA — left-handed zigzag backbone; forms transiently in GC-rich regions; \(12\\ \\\text{bp/turn}\); \(45\\ \\\text{\\AA}/\\text{turn}\) so ~\(3.8\\ \\\text{\\AA}\) between bases; recognized by specific proteins.

DNA melting curve (Tm)

  • Monitors DNA denaturation versus temperature by UV absorbance (260 nm) increasing on strand separation.
  • Tm is the temperature where 50% of DNA is single-stranded.
  • Higher GC content increases Tm because G–C base pairs have three hydrogen bonds and stronger stacking.
  • Tm reflects duplex stability and base composition rather than sequence complexity.

Cot curve (DNA reassociation kinetics)

  • Measures DNA renaturation as a function of the product of initial concentration and time: \(Cot = C_0\\ \cdot\\ t\).
  • Highly repetitive sequences reassociate quickly (low Cot), unique sequences reassociate slowly (high Cot).
  • Useful to estimate genome complexity and relative amounts of repetitive vs unique DNA; longer fragments reassociate more slowly.

Genomic imprinting and DNA methylation

  • Genomic imprinting: parent-specific gene expression caused by epigenetic marks; both paternal and maternal genomes contribute differentially to development.
  • Main molecular mark: DNA methylation at CpG dinucleotides (cytosine methylation).
  • Differential methylation is set during gametogenesis; mouse experiments (gynogenotes vs androgenotes) show both parental contributions are required for normal embryo and placental development.

Plasmid DNA on agarose gel

  • A single plasmid can appear as multiple bands because of different topological forms: supercoiled (compact, migrates faster) and open/relaxed circle (migrates slower).

Plasmid isolation (alkaline lysis + silica column)

  1. Pellet cells by centrifugation and resuspend in buffer.
  2. Lyse with NaOH (denatures DNA) and SDS (solubilizes membranes and proteins).
  3. Neutralize with acetic acid; chromosomal DNA, proteins and lipids precipitate while small plasmids reanneal and stay in solution.
  4. Centrifuge to remove precipitate; apply supernatant to a silica column that binds nucleic acids.
  5. Wash, treat with RNase to remove RNA, then elute purified plasmid DNA.
  6. Check yield and topology by agarose gel electrophoresis.

Transformation (chemical heat-shock method)

  • Make cells competent with cold CaCl2; calcium shields negative charges and helps DNA adhere to the membrane.
  • Use cells in mid-log phase (A_{600} \approx \(0.4\)\(0.6\)) for optimal uptake.
  • Mix plasmid with competent cells, perform a brief heat shock, add recovery medium (LB) and incubate ~45 min at \(37\\ ^{\\circ}\\text{C}\) before plating.
  • Plate on selective medium; only transformed cells carrying the resistance marker form colonies.

Determining cell density (CFU)

  • Perform serial dilutions, plate known volumes, count colonies (CFU) and back-calculate cells per mL.
  • Assumes one viable cell forms one colony; typical E. coli stationary-phase density ≈ \(10^{9}\\ \\\text{cells/mL}\).

Escherichia coli — basic features

  • Gram-negative rod; enteric bacterium of the gut; optimal growth near \(37\\ ^{\\circ}\\text{C}\).
  • Circular chromosome ≈ \(3\\ \times\\ 10^{6}\\ \\\text{bp}\) and can harbor multiple plasmids.
  • Rapid laboratory growth with doubling time ~20–30 min under optimal conditions; growth phases: lag, log, stationary, death.

Antibiotic selection: Ampicillin resistance

  • The AmpR gene encodes beta-lactamase, which degrades ampicillin.
  • Used as a selectable marker: plating on ampicillin selects only transformed cells carrying AmpR.

Restriction enzymes and EcoRI (example)

  • Restriction enzymes are sequence-specific DNases from bacteria that cut at palindromic sites, producing blunt or sticky ends.
  • EcoRI recognizes 5'-GAATTC-3' and makes staggered cuts that produce a 5' overhang.

5' - G A A T T C - 3' 3' - C T T A A G - 5' ↓ ↑ 5' - G + A A T T C - 3' 3' - C T T A A + G - 5'

  • The resulting 5' overhang (e.g., 5'-AATT-3') facilitates annealing and ligation to complementary sticky ends.

R-plasmids (resistance plasmids)

  • Typically small and high copy number (roughly \(10\)\(500\) copies per cell).
  • Carry antibiotic resistance genes as accessory genetic content and an origin of replication (oriR).
  • Confer selective advantage under antibiotic pressure and rely on host replication proteins.

Quick study tips

  • Link each protein-structure level to one keyword: sequence, helix/sheet, fold, assembly.
  • Compare A/B/Z DNA by handedness, bp/turn, and rise per base.
  • Use \(Cot\) kinetics to recall how repeat content affects reassociation speed.