Watson-Crick Model Challenged
By Sean Henahan, Access Excellence
 Rochester,
NY (10/4/97)- A key element of the Watson-Crick Model, that hydrogen
bonding is critical for bonding complementary DNA base pairs, now appears
to be in doubt.
The new study showed that while "Watson-Crick" hydrogen bonds are critical
to the stability of an already existing double helix, they are not needed
for DNA strand synthesis if base pairs possess certain size and shape features.
Eric Kool, professor of chemistry at the University of Rochester
and colleagues devised an ingenious method to test the role of hydrogen
bonding in DNA synthesis. The researchers developed a compound from difluorotoluene,
which is chemically unlike the DNA base thymine but mimics it in terms
of size and shape. Their studies showed that the thymidinie mimic built
from this molecule was inserted efficiently and selectively opposite its
complementary base, adenine, during DNA synthesis reactions, even though
this organic compound made virtually no hydrogen bonds at all with
adenine in existing DNA strands.
"The apparently inescapable conclusion is that H-bonds are not absolutely
required," notes Myron Goodman, a biologist and DNA expert from the University
of Southern California, in an editorial in the Proceedings of the National
Academy of Science. "These results provide an impetus to consider what
role H- bonds actually play in stabilizing DNA and enhancing DNA polymerase
fidelity. ... The notion that H-bonds alone keep the two strands of a DNA
double helix together, found in many textbooks, seems inadequate."
Kool conducted earlier research showing that when thymine is replaced
in a DNA template by difluorotoluene, thymine's normal partner, adenine,
was almost always inserted opposite the molecular impostor. When critics
pointed out that adenine is the base most commonly inserted when any template
base is damaged or missing, Kool turned the tables. He studied whether
a polymerase would insert the mimic itself opposite an adenine template.
Not only was the mimic inserted opposite adenine, it was chosen as adenine's
partner with nearly the same frequency as thymine itself.
"Scientists already know that fluorocarbons such as difluorotoluene
are absolutely terrible at hydrogen-bonding -- in fact, the reason why
nothing sticks to Teflon is because it's a fluorocarbon," Kool says. "With
this finding, if you accept that difluorotoluene doesn't form hydrogen
bonds, then you have to accept that hydrogen bonds aren't necessary for
accurate replication of DNA."
These findings provide a new perspective on the relative roles of hydrogen
bonding and the geometric fit between base pairs in efficient and accurate
DNA replication. The finding are likely to have ramifications far beyond
the theoretical realm, notes Kool. The work could lead to new classes of
drugs that inhibit DNA synthesis which could prove useful in the treatment
of cancer and AIDS.
The research appears in the September 30 issue of the Proceedings
of the National Academy of Science.
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