The motion and structural changes of biomolecules are fundamental to their function, but understanding them at the molecular level has been a major challenge — in part because the crystallography approaches that allowed scientists to study these actions have been extremely time-consuming.
“We can now load up to 10,000 crystals in seconds in our crystallographic silicon chips and have them all line up like eggs in a carton,” says Dwayne Miller, University Professor of Chemistry and Physics at U of T who is also director of the Max Planck Institute for the Structure and Dynamics of Matter in Germany. “A well-defined array of crystal positions allows us to measure the structure at one time point, go to another crystal then come back to the initial crystal and look again. We get orders of magnitude more time points to follow atomic structure details on the relevant time-scale of most biology.”
The journal Nature Methods published the research yesterday.
The new method, which the researchers termed “hit-and-return” (HARE), covers milliseconds to seconds or even minutes. This is of particular interest to biologists and pharmaceutical researchers because the structural changes relevant to a particular biological function or the turnover of a drug happen on such time scales.
The findings were the result of collaboration among several labs. Miller and his team worked with Emil Pai, Professor Emeritus of Biochemistry, Medical Biophysics and Molecular Genetics at U of T, to demonstrate the value of the new method by investigating the action of an enzyme that breaks down human-made pollutants.
Pai in turn worked with colleagues in the Laboratory of Organic Chemistry at ETH Zurich. “The molecule we used as the substrate for the enzyme to work on was difficult to synthesize,” says Pai, who is also an Emeritus Scientist at University Health Network. “Without the synthetic knowledge of our ETH colleagues we would not have had such an excellent system to work on.”
Researchers at the European Molecular Biology Laboratory and Deutsches Elektronen-Synchrotron helped the group by providing access to intense micro-focused X-ray beams at their institutions, and help implementing the hit and return method.
Pai and Miller say the new method has great potential for existing and up-coming high-brilliance synchrotron radiation light sources, which promise to illuminate the atomic structure of biomolecules in even more detail — and now in a far less time-consuming manner.