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Models begin to unravel how single DNA strands combine

09 Oct 2009 - Using computer simulations, a team of University of Wisconsin-Madison researchers has identified some of the pathways through which single complementary strands of DNA interact and combine to form the double helix.
 
Understanding hybridization, the process through which single DNA strands combine to form a double helix is fundamental to biology and central to technologies such as DNA microchips or DNA-based nanoscale assembly. The research by the Wisconsin group begins to unravel how DNA strands come together and bind to each other, says Juan J. de Pablo, UW-Madison Howard Curler Distinguished Professor of Chemical and Biological Engineering.
 
The team published its findings in the Proceedings of the National Academy of Sciences. In addition to senior author de Pablo, the group included David C. Schwartz, a UW-Madison professor of chemistry and genetics, and former postdoctoral research fellow Edward J. Sambriski, now an assistant professor of chemistry at Delaware Valley College in Pennsylvania.
 
The three drew on detailed molecular DNA models developed by de Pablo's research group to study the reaction pathways through which double-stranded DNA undergo denaturation, where the molecule uncoils and separates into single strands, and hybridization, through which complementary DNA strands bind, or "hybridize." In Watson-Crick base pairing, A (adenine) pairs with T (thymine), while G (guanine) pairs with C (cytosine). Reaction pathways are the trajectories single DNA strands follow to find each other and connect via such complementary pairs.
 
The researchers 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 researchers' 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 de Pablo.
 
Results of the team's study show that DNA hybridization is very sensitive to DNA composition, or sequence. "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," he says.