Y. Inokuma and M. Fujita
The technique that revealed DNA's double helix and the shapes of thousands of other molecules is getting an upgrade.
A method described in Nature this week1 makes X-ray crystallography of small molecules simpler, faster and more sensitive, largely doing away with the laborious task of coaxing molecules to form crystals. Instead, porous scaffolding holds molecules in the orderly arrangement needed to discern their structure with X-rays.
"You could call it crystal-free crystallography," says Jon Clardy, a biological chemist at Harvard Medical School in Boston, Massachusetts, who was not involved in the work but wrote a commentary accompanying the paper2.
X-ray crystallography is one of the most important techniques in science, because it is one of only a few ways to directly determine the shape of large molecules. It does this by blasting molecules with X-rays and measuring how their rays are diffracted. Transforming these reflections into molecular models isn’t simple. But cajoling many molecules to crystallize is tedious and time-consuming — like getting a puppy to sit still for a photograph — and, Clardy says, the biggest bottle-neck in X-ray crystallography.
“Some crystallize easily, some crystallize hardly and some are impossible to crystallize, if they are liquid compounds,” says Makoto Fujita, a chemist at the University of Tokyo who led the work along with colleague Yasuhide Inokuma.
Ewen Callaway interviews biological chemist Jon Clardy about the significance of the new technique for deciphering molecular structures.
The team grew materials called metal-organic frameworks, which had large, regularly spaced cavities. These materials acted as 'crystalline sponges', mopping up tiny quantities of small molecules after a short incubation period and holding them in an ordered arrangement within a cage-like scaffold. The sponges were then subjected to X-ray diffraction.
In a blind test, the researchers used their technique to correctly determine the shape of several small molecules, the structures of which were already known. More impressively, the method allowed the authors to determine the structure of miyakosyne A, a chemical made in very small quantities by a species of sea sponge. The molecule has evaded crystallization because its sinewy shape causes it to flop around.
“It’s a remarkable achievement,” says Clardy. He thinks the technique will help researchers to mine marine life, soil bacteria and other organisms for compounds that might have uses in, for example, cancer drugs, because it is often difficult to determine the shape of these molecules from the small quantities found in nature. “I think this could be — to use an overused word — transformational,” Clardy says.
In its current form, the new technique isn’t applicable to proteins, because the pockets in the crystalline sponge are not big enough. But Fujita says his team is trying to make sponges with larger pockets. “Our next grand challenge is to apply this method to protein crystallography,” he says.
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