Researchers establish new way to measure molecules which could help develop new targeted drugs

Worldwide study involving the University of Sheffield has established and standardised a new method to measure exact distances within individual molecules – down to the scale of one millionth of the width of a human hair

The method could help scientists design drugs that are more targeted – potentially benefitting patients with illnesses and diseases that require targeted drug treatment

A worldwide study, involving 20 laboratories including the University of Sheffield, has established and standardized a new method to measure exact distances within individual molecules down to the scale of one millionth of the width of a human hair.

The new method, published in the journal Nature Methods, represents a major improvement of a technology called single-molecule FRET (short for Förster Resonance Energy Transfer), in which the movement and interaction of molecules can be monitored in real time in living cells.

Some molecules in human cells make it tricky for us to see their make-up as they move too quickly, change shape (in order to carry out their essential tasks), and they won’t crystalise, which is the main way scientists are currently able to look at them.

FRET works similarly to proximity sensors in cars: the closer the object is, the louder or more frequent the beeps become. Instead of relying on acoustics, FRET is based on proximity-dependent changes in fluorescence emitted from two labelled molecules and is detected by sensitive microscopes.

Led by Professor Dr Thorsten Hugel of the Institute of Physical Chemistry and the BIOSS Centre of Biological Signalling Studies, the 20 laboratories involved in the study refined a method so that scientists using different microscopes and analysis software obtained the same distance measurements, even in the subnanometer range.

Professor Dr Hugel said: “This study is an important step towards achieving accurate models of the remarkable structural dynamics of biomolecules, and also towards understanding how these structural changes determine the activity and function of molecules.”

Proteins are an example of molecules that can be investigated using this technique. Their molecules are so small that up to one million of them lined up side-by-side would fit across a 2mm grain of sand.

Dr Timothy Craggs, Lecturer in Chemical Biology in the University of Sheffield’s Department of Chemistry, said: “This new method means a significant advancement in our ability to study molecules, going beyond other established structural techniques like x-ray crystallography.

“It allows us to look at the components of cells without them being in crystal form, and one molecule at a time, which is how they operate when in the cell.

“This will ultimately allow us to design drugs that are much more targeted and block the specific movement or shape change of components in a cell that are causing an issue. It is therefore a development that may benefit every single illness and disease requiring targeted drug treatment.”

Read the article in Nature Methods volume 15, pages 669–676 (2018)

Part of this research was carried out using a research-grade microscope built by two University of Sheffield chemistry and physics undergraduates.

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