Physicists Demonstrate Precise Manipulation Of DNA-Drug Interactions

This research, performed primarily by graduate student Thaya Paramanathan, published in a recent edition of the Journal of the American Chemical Society (vol. 130, p. 3752), has the potential to uncover crucial information about how to target DNA in order to develop therapies for chronic diseases such as cancer and AIDS.

DNA, the structure that holds the human genetic code, is composed of nucleic acid bases pairing up and bonding together to form a double helix. Intercalators are molecules that bind between DNA base pairs and have been found to inhibit cell replication, a highly desired quality for potential drug targets. Novel “threading” intercalators have recently been developed to optimize DNA binding. Due to the strength of these bonds and the slow rate of binding, however, it is hard to study the interactions of these intercalators using normal methods, resulting in a limited availability of data and research options.

To address these issues, Mark Williams and his team stretched single DNA molecules using optical tweezers to better control the interactions between the DNA and the potential drug target molecules.

“By studying this threading mechanism on a single DNA molecule, we were able to directly measure the physical characteristics of the interactions between the DNA and potential DNA binding drugs,” said Williams.

The optical tweezers grab the ends of the DNA strand and stretch it out, allowing for the DNA strands to separate more quickly. When the DNA bases separate, the drug molecule, which is dumbbell-shaped and binds with the DNA in the center of the dumb-bell, slides in between the base pairs. When the bond re-forms between the base pairs, the potential drug molecule remains stuck between the DNA strands that form the double helix, and therefore it has formed a very strong bond.

The observations lead to the understanding of how and under what circumstances these bonds occur, which can help in the development of drug therapies that would inhibit or prevent mutated cells from replicating.

“The ability to precisely quantify and characterize the physical mechanism of this threading intercalation should help to fine-tune the desired DNA binding properties,” added Williams.