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Key To Understanding Protein-DNA Interactions? Simply 'Unzip' It, Say Cornell Biophysicists Of Double Helix

Date:
July 15, 2003
Source:
Cornell University
Summary:
Fifty years after Watson and Crick described the structure of double helix DNA, Cornell University biophysicists are discovering the roles of DNA-binding proteins in much the same way an impatient person frees a stuck zipper.

ITHACA, N.Y. -- Fifty years after Watson and Crick described the structure of double helix DNA, Cornell University biophysicists are discovering the roles of DNA-binding proteins in much the same way an impatient person frees a stuck zipper.

Not exactly brute force -- but rather carefully metered dynamic force -- is the key to pulling apart two strands of the DNA "zipper" and popping loose restriction enzymes and other proteins along the way. A report in the journal Physical Review Letters (PRL Vol.91, No.2, July 11, 2003) by Steven J. Koch and Michelle D. Wang, titled "Dynamic Force Spectroscopy of Protein-DNA Interactions by Unzipping DNA," tells how to do it and predicts future applications of the technique.

"This could be used for restriction mapping, the first critical step in genomic sequencing, and for actual sequencing where the sequence of DNA is determined with a large number of restriction enzymes," says Wang, Cornell assistant professor of physics, of a handy technique with an unwieldy name: unzipping force analysis of protein association, or UFAPA.

"We're still in the laboratory-development stage now," Wang adds, "but the process could be automated so that in drug development, for example, pharmaceutical companies could use UFAPA to screen libraries of small molecules for affinity to DNA." The other PRL author, Koch, was a physics graduate student at Cornell at the time of the research and now is a postdoctoral researcher at Sandia National Laboratories.

UFAPA is simplicity itself, given the right equipment and a light touch on the controls. As described in the PRL report:

One strand of the DNA is anchored to a microscope cover slip; the other strand is attached to a microsphere (a tiny ball of polystyrene) that is held in an optical trap (by a laser beam); the DNA is unzipped as the microscope cover slip is moved away from the trapped microsphere; when the unzipping fork in the DNA reaches a bound protein molecule, a dramatic increase in the tension in the DNA followed by a sudden tension reduction is detected; and finally analyses of the unzipping forces and length of the DNA tether reveal the locations of bound proteins and the equilibrium association constants. Those analyses are the "spectroscopy" part of the process, Wang explains. Different proteins yield to different characteristic forces and the researchers are filling out a dynamic-force spectrum as they learn which is which. Better yet, the double helix rezips as soon as tension is relaxed so that the same bit of DNA can be recycled again and again with numerous proteins.

After working on the technique for nearly three years, Wang has applied for a patent through the Cornell Research Foundation. Among other possible applications of UFAPA, she says, are these:

* locating binding sites of a DNA binding protein whose binding sites are yet unknown;

* detecting new DNA binding proteins for binding to specific sequences;

* distinguishing between different forms of a bound protein, such as phosphorylated or unphosphorylated, methylated or unmethylated; and

* conducting rapid assays of binding affinities and strengths of molecules designed to bind to specific sequences of DNA for therapeutic purposes.

The research reported in the PRL article was conducted with support from the National Institutes of Health, the Beckman Young Investigator Award, Alfred P. Sloan Research Fellow Award and the Keck Foundation's Distinguished Young Scholar Award.


Story Source:

The above story is based on materials provided by Cornell University. Note: Materials may be edited for content and length.


Cite This Page:

Cornell University. "Key To Understanding Protein-DNA Interactions? Simply 'Unzip' It, Say Cornell Biophysicists Of Double Helix." ScienceDaily. ScienceDaily, 15 July 2003. <www.sciencedaily.com/releases/2003/07/030715091326.htm>.
Cornell University. (2003, July 15). Key To Understanding Protein-DNA Interactions? Simply 'Unzip' It, Say Cornell Biophysicists Of Double Helix. ScienceDaily. Retrieved August 22, 2014 from www.sciencedaily.com/releases/2003/07/030715091326.htm
Cornell University. "Key To Understanding Protein-DNA Interactions? Simply 'Unzip' It, Say Cornell Biophysicists Of Double Helix." ScienceDaily. www.sciencedaily.com/releases/2003/07/030715091326.htm (accessed August 22, 2014).

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