Research chemists have a found a class of synthetic molecules that could quite literally act as a key which could lock away sections of DNA into a closely wound coil preventing proteins from interacting with particular sections of DNA code. By locking up the DNA in this way scientists could stop particular sequences of DNA from activating biological changes that doctors or scientists would rather avoid, or wish to regulate closely.
Until now researchers trying to devise synthetic molecules that would bind to DNA have typically only been able to produce small molecules that because of their size prefer to bind to the smaller, or minor, groove in the structure of DNA. These small molecules have also only really been able to stretch across a couple of DNA base pairs.
But now Dr. Mike Hannon & Dr. Alison Rodger, research chemists at the University of Warwick, have produced a large synthetic molecule, a Supramolecular Cylinder, which binds to the major groove of DNA, rather than the minor one, and with surprising results.
When it binds to the major DNA groove the new synthetic molecule bends the particular section of DNA it is attached to. The DNA became tightly coiled together in a manner resembling the way non synthetic molecules package DNA together into chromosomes.
The ability of this synthetic molecule to coil up DNA could be used to lock up sequences of DNA so that they do not link with proteins to signal particular biological changes, thus giving scientists new tools to use in gene regulation. The strong binding mechanism to the major grove could also be used to enhance treatments that use drugs that act on DNA as such drugs must be delivered not only into the correct cell but into the nucleus as well.
The next task for the researchers will be to increase the sensitivity of the synthetic molecule to ensure that it can be used to bind to very specific DNA sequences and thus be used as a more precise tool. Currently the synthetic molecule seeks out and stretches across a sequence of 5 DNA base pairs. The researchers are now working to extend it until they reach a point at which it will target a 15 base pair sequence.
The particular Supramolecular Cylinder, [Fe2L3]4+, is an iron triple helicate with three organic strands wrapped around two iron centres to give the cylinder shape (a metallo-supramolecular cylinder) which neatly fits within a DNA helix. Indeed the Supramolecular Cylinder is about the same size as the parts of a protein that recognise and bind with particular sections, or sequences, of DNA. The high positive charge of the Supramolecular Cylinder also enhances its ability to bind to DNA which is negatively charged. The molecule that the researchers devised has two mirror image forms (or enantiomers). The P enantiomer did still bind to the outside of the minor groove of DNA but its mirror image (the M enantiomer) preferred to bind inside the major groove of DNA.
The work is published on 16th April 2002 in a paper entitled "Intramolecular DNA coiling mediated by metallo-supramolecular cylinders: differential binding of P and M helical enantiomers" in Proceedings of the National Academy of Sciences, USA which can be found on the PNAS web site web site at http://www.pnas.org from 16th April.
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