Dance of the molecules

New method tracking single atoms may lead to improved drug design

Until now, scientists studying the workings of ultra-microscopic forms have had to rely on the scientific equivalents of still photos, something like trying to fathom driving by looking at a photograph of a car. Now, Prof. Irit Sagi and her team of the Structural Biology Department are using new and innovative methods developed at the Weizmann Institute to see real-time “video clips” of enzyme molecules at work. The resolution of these animated clips is so fine that the scientists are able to see the movements of individual atoms within the molecule.

The challenge facing the Weizmann team was to capture, step-by-step, the complex process — the whole of which takes place in a tiny fraction of a second — that an enzyme molecule goes through as it performs its work. Their pioneering method was published in Nature Structural Biology. It was hailed as the first of its kind, and a potentially important tool for biophysicists.

To obtain the “live action” footage, Sagi and her team use a technique akin to stop-action photography, but on an infinitely smaller scale. They literally freeze the process at certain stages, using advanced methods of chemical analysis to determine the exact molecular layout at each stage. The most difficult part, says Sagi, was figuring out the correct time frames that would allow them to see each phase of enzyme activity clearly. She compares it to attempting to capture on film the swirling of syrup being mixed into cake batter – one has to gauge at what points individual stages of the process will be most visible.

Building an animated sequence from individual frames, the scientists are granted a rare peek into the intricate dance of life on the molecular level. “This method,” says Sagi, “represents more than a major breakthrough in the techniques used to understand enzyme activity. It changes the whole paradigm of drug formulation. Now we can precisely identify which parts of the molecule are the active regions (those which directly perform tasks), and the exact permutations of these molecular segments throughout the whole process. New, synthetic drugs can be designed to target specific actions or critical configurations.”

Sagi’s team is doing just that for one enzyme family known to play a role in cancer metastasis. Matrix metalloproteinases (MMPs), assist the cancer cells’ escape and entry into new tissues by breaking down the structural proteins that keep cells in place, a skill normally needed to clear out tissue in preparation for growth or repair. Using the knowledge gained by the new technique, the team designed a molecule to block MMPs at one crucial step in their dance.

Prof. Irit Sagi’s research is supported by the Avron-Wilstaetter Minerva Center; the Helen and Milton A. Kimmelman Center for Biomolecular Structure and Assembly; the Ceil and Joseph Mazer Center for Structural Biology; the Jakubskind-Cymerman Prize; the Laub Fund for Oncogene Research; Prof. Clotilde Pontecorvo, Italy; and Verband der Chemischen Industrie.