Some of the pathways through which single complementary strands of DNA interact and combine to form the double helix have been identified. University of Wisconsin-Madison researchers used computer simulations to discover that DNA hybridization is very sensitive to its composition. The team published their findings October 5 in the Proceedings of the National Academy of Sciences.
The investigators were looking at reaction pathways through which double-stranded DNA undergoes denaturation, where the molecule uncoils and separates into single strands, and hybridization, through which complementary DNA strands bind. They studied both random and repetitive base sequences.
Random sequences of the four bases A, T, G, and C contained little or no regular repetition. To the scientists' surprise, a couple of bases located toward the center of the strand associate early in the hybridization process. The moment they find each other, they bind, and the entire molecule hybridizes rapidly and in a highly organized manner.
Conversely, in repetitive sequences, the bases alternated regularly, and the group found that these sequences bind through a so-called diffusive process. "The two strands of DNA somehow find each other, they connect to each other in no particular order, and then they slide past each other for a long time until the exact complements find one another in the right order, and then they hybridize," says senior author, Juan J. de Pablo, Ph.D., UW-Madison Howard Curler distinguished professor of Chemical and Biological Engineering. "Contrary to what was thought previously, we found that the actual process by which complementary DNA strands hybridize is very sensitive to the sequence of the molecules."
Knowledge of how the process occurs could enable researchers to more strategically design technologies such as gene chips. For example, says Dr. de Pablo, if a researcher wanted to design sequences that bind very rapidly or with high efficiency, he or she could place certain bases in specific locations so that the hybridization reaction could occur faster or more reliably.
Ultimately, the research could help biologists understand why some hybridization reactions are faster or more robust than others. "One of the really exciting things about this work is that the hybridization reaction between two strands of DNA is really fundamental to life itself," says Dr. de Pablo. "It is the basis for much of biology. And it is amazing to me that, until now, we knew little of how this reaction actually proceeds."