Experiment

Plasmid Extraction (TIANGEN Mini Plasmid Kit Protocol)


Preparations

  • Ensure RNase A has been added to Buffer P1.
  • Add the specified volume of absolute ethanol to Buffer PW.

Steps

  1. Column Equilibration: Add 500 µl Buffer BL to a CP3 Spin Column (in a Collection Tube). Centrifuge at 12,000 rpm for 1 minute. Discard the flow-through. Place the column back in the tube.
  2. Harvest Cells: Centrifuge 1-5 ml bacterial culture at 12,000 rpm for 1 minute. Discard the supernatant completely.
  3. Resuspend Pellet: Add 250 µl Buffer P1 to the pellet. Resuspend completely by pipetting or vortex until no cell clumps remain.
  4. Lysе Cells: Add 250 µl Buffer P2. Mix gently by inverting the tube 6-8 times. The solution should become clear and viscous. Do not vortex. Do not allow lysis to proceed for more than 5 minutes.
  5. Neutralize: Add 350 µl Buffer P3. Mix immediately and gently by inverting 6-8 times. A white precipitate will form. Centrifuge at 12,000 rpm for 10 minutes.
  6. Bind DNA: Transfer the supernatant from Step 5 to the equilibrated CP3 Spin Column. Avoid transferring any precipitate. Centrifuge at 12,000 rpm for 30-60 seconds. Discard the flow-through. Place the column back in the tube.
  7. Wash (1): Add 600 µl Buffer PW to the column. Centrifuge at 12,000 rpm for 30-60 seconds. Discard the flow-through. Place the column back in the tube.
  8. Wash (2): Repeat Step 7.
  9. Dry Membrane: Centrifuge the empty column at 12,000 rpm for 2 minutes to dry it. Optional: Open the column lid and let it air-dry at room temperature for 2-5 minutes to ensure all ethanol evaporates (remaining ethanol may affect enzyme reaction, including PCR).
  10. Elute DNA: Place the column in a clean 1.5 ml microcentrifuge tube. Add 50-100 µl Buffer EB (we use ddH2O, pH 7.0-8.5, as buffer to DNA sequencing) directly to the center of the membrane. Let it stand at room temperature for 2 minutes. Centrifuge at 12,000 rpm for 2 minutes to collect the purified plasmid DNA.

PCR Amplification


Preparations

  • 25ul PCR tube
  • 2x PCR mix (including 2x dNTP, 2x Taq DNA polymerase, 2x PCR Buffer)
  • plasmid samples (see "Phase 1 Construction" for details.)
  • corresponding primers (see "Phase 1 Construction" for details)
  • PCR instruments

Reaction System

Component Volume
2x PCR mix 12.5ul
Primer Front/Back 0.5ul each
DNA 1ul
ddH2O 10.5ul
Total 25ul

PCR Conditions

The duration of the PCR reaction varies depending on the length of the specific target fragment. For segments of target DNA with less than 1000 base pairs (bp), the DNA polymerase needs to operate for 40 seconds. For the remaining segments which are approximately 6000 bp, the DNA polymerase needs to work for 5 minutes. The entire process is set up as follows:

95℃ 95℃ 58℃ 72℃ 72℃ 4℃
5min 1min 40s/5min 1min 8min
1 time 30 times 1 time

DNA Electrophoresis


Preparations

  • Agarose powder
  • 1× TAE buffer (50 mL)
  • Loading Buffer (6×, Takara)
  • DNA stain (GelStain, 10,000×, Trans)
  • DNA samples (e.g., PCR products)
  • DNA marker (10 μL)
  • Electrophoresis apparatus and power supply

Steps

  1. Prepare the Gel: Weigh 0.75 g agarose (actual weight is depend on the length of DNA fragment, the quality ranges from 0.5 percent for long fragments to 1.5 percent for short fragments) and dissolve it in 50 mL of 1× TAE buffer. Heat the mixture (e.g., in a microwave) until the agarose is completely dissolved.
  2. Add DNA Stain: After the solution cools to about 60°C, add GelStain (10,000×) at 5 μL per 50 mL gel. Mix gently to avoid bubbles.
  3. Cast the Gel: Pour the molten agarose into the gel casting tray with combs in place. Allow it to solidify at room temperature for about 15 minutes.
  4. Prepare Samples: Mix the PCR products with 6× Loading Buffer at a 1:5 ratio (e.g., 20 μL sample + 4 μL buffer). Mix gently and briefly spin down if there are bubbles in it.
  5. Run the Gel: Place the solidified gel in the electrophoresis tank and add enough 1× TAE buffer to cover it. Load the DNA marker (10 μL) and the prepared samples into the wells. Run electrophoresis at constant voltage (e.g., 120 V) until the dye front migrates about 3/4 of the gel length.
  6. Visualize the DNA: Observe the gel under a UV transilluminator.

DNA Electrophoresis Recovery (TIANGEN Gel Purification Kit)


Preparation

Add absolute ethanol to Buffer PW as indicated on the bottle.

Steps

  1. Column Equilibration: Add 500 µl Buffer BL to a CB2 Spin Column (placed in a Collection Tube). Centrifuge at 12,000 rpm (~13,400×g) for 1 min. Discard the flow-through. Place the column back in the collection tube.
  2. Gel Excission: Excise the target DNA band from the agarose gel and transfer it to a clean tube. Weigh the gel slice.
  3. Dissolve Gel: Add a volume of Buffer PC equal to the gel weight (100 µl for 0.1 g). Incubate at 50°C for ~10 min, mix intermittently by inverting the tube until the gel is completely dissolved.
  4. Bind DNA: Apply the dissolved gel solution to the CB2 column. Centrifuge at 12,000 rpm for 1 min. Discard the flow-through. Place the column back in the collection tube.
  5. Wash (1): Add 600 µl Buffer PW to the column. Centrifuge at 12,000 rpm for 1 min. Discard the flow-through. Place the column back in the collection tube.
  6. Wash (2): Repeat Step 5.
  7. Dry Column: Centrifuge the empty column at 12,000 rpm for 2 min. Air-dry the column at room temperature for 2-5 min with the lid open.
  8. Elute DNA: Place the column in a clean 1.5 ml microcentrifuge tube. Add 30-100 µl Buffer EB (we use ddH2O, pH 7.0-8.5, as buffer to DNA sequencing) directly to the center of the membrane. Incubate at room temperature for 2 min. Centrifuge at 12,000 rpm for 2 min to collect the purified DNA.

Gibson Assembly


The volume ratio is as follows:

Component Volume Amount
2x ClonExpress Mix 5ul
Linearization carrier X ul (50-100ng) 0.02-0.5pmol
Insertion element Y ul (The mole ratio usually is: carrier: insertion = 1:2 to 1:5) 0.04-0.2pmol
ddH20 Make up to 10ul

Place the reaction tube in the PCR machine and let it react at 50℃ for 30 to 60 minutes. After the reaction is complete, the product needs to be placed on ice immediately to cool. Process "Bacterial Conversion" subsequently.


Bacterial Transformation


Preparations

  • Plasmid DNA: Purified plasmid (e.g., extracted using TIANGEN kits).
  • Competent Cells: Chemically competent cells (e.g., DH5α+BL21(DE3)), stored at -80°C and thawed rapidly on ice before use.
  • Sterile Medium: LB liquid medium without antibiotics (for recovery).
  • Selective Plates: LB solid plates containing the appropriate antibiotic (e.g., Kana, Amp)
  • Pre-chilled Equipment: Centrifuge pre-cooled to 4°C, ice bucket prepared.
  • Sterile Consumables: 1.5 mL centrifuge tubes, pipette tips.

Steps

  1. On-Ice Handling: Take a tube (typically 50-100 µL) of competent cells and place it on ice to thaw completely. Gently mix the competent cells.
  2. Adding Plasmids: Add 1 µL of ligation product or plasmid DNA to the competent cells (volume should not exceed 1/10 of the competent cell volume). Mix gently by pipetting (Do not vortex!).
  3. Ice Incubation: Incubate the mixture on ice for 30 minutes.
  4. Heat Shock: Quickly transfer the tube to a 42°C water bath for precise heat shock for 60-90 seconds.
  5. Ice Cooling: Immediately return the tube to ice and incubate for 2-5 minutes.
  6. Recovery: Add 450 µL of sterile, antibiotic-free LB liquid medium to the tube. Place the tube in a 37°C shaker and incubate at 150-200 rpm for 45-60 minutes to allow cell recovery and antibiotic resistance gene expression.
  7. Plating: Briefly centrifuge the recovered culture (e.g., 4000 rpm, 1 min), aspirate part of the supernatant, leaving about 100 µL, and resuspend the cells by pipetting. Transfer all or part (e.g., 100 µL) of the culture to an LB plate containing the appropriate antibiotic. Spread evenly using a sterile spreading rod.
  8. Incubation and Observation: After the culture is fully absorbed by the plate, invert the plate and incubate in a 37°C incubator overnight (12-16 hours). Check for single colonies the next day.

Protein-induced Expression


Seed Culture Preparation

Obtain seed solution: On an LB solid agar plate (100mg/L K antiseptic), inoculate and cultivate for 16-18 hours. Select single colonies with good growth and perform single cloning into 5ml liquid TB medium then cultivate at 37℃, 220rpm shaking incubator for 12 hours. In a 250 mL conical flask, inoculate 50 mL of TB medium with bacterial solution corresponding to 3% of the medium volume (100mg/L K antiseptic), cultivate at 37℃, 220rpm shaking incubator.

Induction

Measure the OD value of the shaking-cultured bacterial solution once every hour (add 0.02% volume of defoamer). When OD = 4 (note: dilute according to the range of the instrument), start induction. Add xxx% IPTG (used as experimental variable), induce for xxx hours under same cultivating conditions.

Collection

Centrifuge to collect the bacteria. Prepare for ultrasonic disruption and protein electrophoresis detection.

Test Protein Production

After induction, centrifuge the fermentation broth to collect the cells. Resuspend the pellet in an appropriate amount of protein loading buffer, incubate in a water bath at 100°C for 10 min, and then centrifuge to obtain the supernatant for loading. Pipette the samples into the wells of the protein gel. Set the electrophoresis apparatus at 80 V; once the samples pass the interface between the stacking gel and separating gel, increase the voltage to 120 V. Continue electrophoresis for approximately 45 min until the dye front is about 1 cm from the bottom of the gel, then stop the run.


Ultrasonication


Place the precipitated cells in an ice bath beaker. Resuspend the precipitated cells in pre-cooled lysis buffer (e.g., 20 mM Tris-HCl, pH 8.0). Extract part of bacterial suspension for ultrasonication and leave the rest for later use. Adjust the ultrasonic probe to a distance of approximately 1 cm from the bottom of the tube. Set the ultrasonic cell disruptor to the following parameters: 25% power, 3s ON, 17s OFF. Run for 20 minutes. Ensure that no significant noise or screeching sound occurs after initiation.


Protein Electrophoresis


Add the protein loading buffer, and incubate in a boiling water bath for 10 minutes before loading. Set the electrophoresis apparatus to 80V. When the bands enter the separation gel, increase the voltage to 120V.

Gel Preparation

Prepare a 12% resolving gel and a 4% stacking gel using the Laemmli system.

  • Resolving gel (12%): Mix 4.0 mL of 30% acrylamide/bis solution, 2.5 mL of 1.5 M Tris-HCl (pH 8.8), 100 µL of 10% SDS, 100 µL of 10% APS, 4 µL of TEMED, and add deionized water to a final volume of 10 mL. Pour between clean glass plates, overlay with isopropanol, and allow to polymerize for ~30 minutes.
  • Stacking gel (4%): Mix 0.67 mL of 30% acrylamide/bis, 0.83 mL of 0.5 M Tris-HCl (pH 6.8), 33 µL of 10% SDS, 33 µL of 10% APS, 3 µL of TEMED, and water to a total of 5 mL. Pour on top of the polymerized resolving gel, insert the comb, and allow to solidify for ~20 minutes.

Sample Preparation

Mix each protein sample with 5× SDS loading buffer in a 4:1 ratio. Boil the mixture at 100 °C for 10 minutes to denature proteins, then briefly centrifuge to collect the condensate.

Gel Assembly and Buffer Filling

Assemble the gel in the electrophoresis tank and fill the inner and outer chambers with 1× Tris-Glycine-SDS running buffer, ensuring no leaks.

Sample Loading

Carefully remove the comb and rinse the wells with buffer. Load 5--20 µL of each denatured protein sample into individual wells along with a molecular weight marker.

Electrophoresis

Run the gel at 80 V through the stacking gel until the dye front reaches the resolving gel, then increase the voltage to 120 V. Continue until the dye front is about 1 cm from the gel's bottom (about 45--60 minutes).

Staining

Remove the gel from the glass plates and immerse it in Coomassie Brilliant Blue R-250 staining solution (0.1% dye in 50% methanol and 10% acetic acid). Gently shake for 60 minutes.

Destaining

Replace the staining solution with destaining buffer (10% methanol, 10% acetic acid). Gently agitate until the gel background becomes clear and the protein bands are sharply visible.

Imaging

Rinse the gel briefly with water to remove residual destaining solution, then capture images of the protein bands using a gel imaging system for record and analysis.


Protein Purification


Preparations

  • Chromatography Column: 3 mL Ni-NTA Resin
  • Sample: Crude cell lysate containing the His-tagged protein.
  • Equilibration Buffer: 20 mM Tris-HCl, pH 7.4-8.0
  • Wash Buffer: 20 mM Tris-HCl, 20 mM Imidazole, pH 7.4-8.0
  • Elution Buffer: 20 mM Tris-HCl, 500 mM Imidazole, pH 7.4-8.0
  • Cleaning & Storage Solutions: 20 mM Tris-HCl (pH 7.4-8.0), Distilled Water, 20% Ethanol

Steps

  1. Column Preparation: Rinse the nickel column with pure water, and then equilibrate with the binding buffer (20 mM Tris-HCl).
  2. Sample combination: Slowly allow the supernatant after centrifugation to flow through the column, allowing the target protein with His tag to specifically bind to the nickel column. This is the device we designed for fixed filtration.
  3. Remove impurities: Rinse the column with 10-15 times the column volume of the washing buffer (20 mM Imidazole) to remove the unbound and non-specifically bound contaminants.
  4. Elution of target protein: The eluate was collected by stepwise or linear gradient elution with elution buffer (500 mM Imidazole).

Detailed Protocol

  1. Resin Preparation
    • Transfer the Ni-NTA resin slurry (stored in ethanol) to a 15 mL centrifuge tube.
    • Add 3 volumes of distilled water and mix thoroughly.
    • Centrifuge at 2000 rpm for 2 minutes. Carefully decant the supernatant.
    • Repeat this washing step a total of 3 times to completely remove the ethanol.
    • Critical Note: Never let the resin dry out during preparation or the entire procedure.
  2. Column Packing & Equilibration
    • Pour the prepared resin slurry into the affinity column and allow it to settle by gravity.
    • Pass 5 column volumes (CV) of Equilibration Buffer through the column at a moderate flow rate (approximately 3-4 seconds/drop).
    • This step ensures the column environment is optimal for protein binding.
  3. Sample Loading
    • Slowly load the protein sample onto the top of the column.
    • Maintain a slow flow rate of about 10 seconds/drop to maximize binding of the target protein to the nickel ions.
    • Collect the initial flow-through and label it Ft1. Save a 200 µL aliquot for analysis.
    • To increase binding efficiency, reload the Ft1 onto the column. Collect subsequent flow-through fractions, Ft2 and Ft3, saving 200 µL of each for analysis.
  4. Washing
    • Pass 5 CV of Wash Buffer through the column.
    • The flow rate can be increased to the maximum rate for this step.
    • This removes weakly and non-specifically bound contaminating proteins.
    • Collect the wash fractions in steps, labeling them W1, W2, W3. Save a 200 µL aliquot of each for analysis.
  5. Elution
    • Pass 5 CV of Elution Buffer through the column.
    • Return to a moderate flow rate (approximately 3-4 seconds/drop).
    • The high concentration of imidazole competitively displaces the His-tagged protein from the nickel ions.
    • Collect the eluate in 1 mL fractions, labeling them E1, E2, E3, etc. Save a 200 µL aliquot of each for analysis.
  6. Column Regeneration & Storage
    • Wash the column with 5 CV of distilled water.
    • Pass 5 CV of 20% ethanol through the column to prevent microbial growth.
    • Store the column at 4°C with the ends capped.
  7. Sample Analysis
    • Analyze all saved fractions (Ft1-3, W1-3, E1-3) by SDS-PAGE to assess purification efficiency and identify the fractions containing the pure target protein.
    • Combine the purest elution fractions and proceed to dialysis or buffer exchange as needed for downstream applications.