The fourth and fifth generation DNA sequencers
Here is the article that gave me idea:
Room-temperature AFM gets picoscale stability
Basically the authors of the study have a way to get picoscale resolution from the cantilever tip of an AFM. With this they can feel each base of the strand and determine its nature. By using magnetic beads and magnetic fields or laser tweezers to straighten and immobilize the strand, the process can be made semi-high throughput. Using this technique accuracy can be nearly prefect with read lengths in the 100-1,000s of kilobases (limited only by the platform size and difficulty of straightening and holding long stretches of DNA.)
Similarly proteins and other biomolecules can be sequenced, by straightening them and running the tip over the amino acids or other monomers to determine their nature and if they are modified, etc.
For the fifth generation DNA sequencer the tip will slide in one of the groves (probably major) and read the bases the same way a needle reads the groves in a record. If this is impractical the fourth generation method can be improved by having the tip contact only the edges of the single stranded nucleotides so that it can “feel’ the bond energy. This is still faster than the fourth generation method since the scan is linear, since reading the other atoms in the base is not necessary. However, reading the bond energy requires a much more complex and sensitive data recording system.
Additionally this method could make X-ray crystallography and NMR somewhat obsolete. By feeling the structure of the folded protein the tip can determine a maximum volume, and use the surface texture to determine the location of domains and individual residues. Then by adding the binding partners or substrates the tip can be used to measure the conformational changes of the protein in semi-real time. (By constraining the protein’s movement with the tip, a whole new world is opened up for biochemists; intermediate steps in enzymatic reactions can be captured, etc.)
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