Paper Pub­lished in New Issue of Nature Methods

North­eastern Uni­ver­sity pro­fessor Mark C. Williams and grad­uate stu­dent Ioana Vladescu have dis­cov­ered a novel method for studying the DNA binding of small mol­e­cules with unprece­dented accu­racy. Their paper, titled “Quan­ti­fying force-​​dependent and zero-​​force DNA inter­ca­la­tion by single-​​molecule stretching,” has been pub­lished in the June 2007 issue of the pres­ti­gious Nature Methods.

Because mol­e­cules that bind through inter­ca­la­tion (a type of binding) may inter­fere with impor­tant bio­chem­ical processes in repli­cating cells, this method may be a useful tool for rational drug design tar­geting cancer, AIDS and other diseases.

In order to develop new drugs to treat cancer and other dis­eases, sci­en­tists need to better under­stand if and how these drugs will bind to DNA,” says Williams. “This new method allows us to examine inter­ca­la­tion in unprece­dented and exquisite detail.”

Williams and col­leagues used single DNA mol­e­cule stretching to inves­ti­gate DNA inter­ca­la­tion by ethidium and three ruthe­nium com­plexes. By mea­suring ligand-​​induced DNA elon­ga­tion at dif­ferent ligand con­cen­tra­tions, they deter­mined the binding con­stant and site size as a func­tion of force. Both quan­ti­ties depend strongly on force and, in the limit of zero force, con­verge to the known bulk solu­tion values, when available.

This approach allowed the team, com­prised of Williams, Vladescu and North­eastern col­league Micah McCauley, along with Megan Nunez from Mt. Holyoke Col­lege, and Ioulia Rouzina from the Uni­ver­sity of Min­nesota to dis­tin­guish the inter­cala­tive mode of ligand binding from other binding modes and allowed char­ac­ter­i­za­tion of inter­ca­la­tion with binding con­stants ranging over almost six orders of mag­ni­tude, including lig­ands that do not inter­ca­late under exper­i­men­tally acces­sible bulk solu­tion con­di­tions. As ligand con­cen­tra­tion increased, the DNA stretching curves sat­u­rated at the max­imum amount of ligand inter­ca­la­tion. The results showed that the applied force par­tially relieves normal inter­ca­la­tion con­straints. The team also char­ac­ter­ized the flex­i­bility of intercalator-​​saturated dsDNA for the first time.

Williams and his col­leagues are con­tin­uing their research and plan to start testing actively used cancer drugs in the near-​​term.

Nature Methods is a Nature Research Journal that serves as a forum for the pre­sen­ta­tion of novel bio­chem­ical and bio­phys­ical research methods of rel­e­vance to the bio­log­ical and bio­med­ical sciences.

For more infor­ma­tion, please con­tact Laura Shea at 617–373-5427 or l.​shea@​neu.​edu.

About North­eastern:

Founded in 1898, North­eastern Uni­ver­sity is a pri­vate research uni­ver­sity located in the heart of Boston. North­eastern is a leader in inter­dis­ci­pli­nary research, urban engage­ment, and the inte­gra­tion of class­room learning with real-​​world expe­ri­ence. The university’s dis­tinc­tive coop­er­a­tive edu­ca­tion pro­gram, where stu­dents alter­nate semes­ters of full-​​time study with semes­ters of paid work in fields rel­e­vant to their pro­fes­sional inter­ests and major, is one of the largest and most inno­v­a­tive in the world. The Uni­ver­sity offers a com­pre­hen­sive range of under­grad­uate and grad­uate pro­grams leading to degrees through the doc­torate in six under­grad­uate col­leges, eight grad­uate schools, and two part-​​time divi­sions. For more infor­ma­tion, please visit www​.north​eastern​.edu.