Physicists have developed a "ruler" that can measure intramolecular distances with precision down to the size of an atom.

Proteins are very large molecules (macromolecules) composed of carbon, hydrogen, nitrogen, and oxygen atoms that form a variety of amino acids linked together by peptide bonds. Sometimes, the structure of a protein is disrupted, leading to changes in its shape, which can affect the function of these macromolecules. Some structural alterations in proteins can trigger the development of a range of diseases; for example, a change in the structure of tau protein, which is responsible for the proper functioning of neurons, can provoke Alzheimer's disease.

To anticipate impending structural changes in proteins and understand the processes responsible for these changes, it is crucial to determine the precise distances between atoms (and clusters of atoms) within these macromolecules.

A team of German physicists led by Steffen Sahl from the Max Planck Institute for Multidisciplinary Sciences has developed an intramolecular "ruler" called MINFLUX, capable of measuring distances within proteins ranging from 0.1 nanometers (angstroms) to 10 nanometers, depending on the protein's structure. The researchers shared their findings in a paper published in the journal Science.

To create the intramolecular "ruler," Sahl and his colleagues utilized fluorescence, which is the process that allows molecules to emit light upon absorbing a quantum of light. The physicists attached two small fluorescent molecules (labeled with photoactivatable dyes) to two different locations on the macromolecule and then illuminated them with a laser beam. By analyzing the light emitted by the glowing molecules, the researchers were able to measure the distance between them.

This method was used to measure the intramolecular distance for several proteins, with the smallest measuring just 0.1 nanometers—the size of a single atom. The fluorescent "ruler" also provided results up to 10 nanometers, which indicates a broader range of measurements than many traditional optical methods.

In one example, the researchers examined two different structures of the same protein and discovered that they could distinguish between them: these structures were located at different distances from each other—one nanometer and four nanometers, respectively. In another experiment, the scientists measured the intramolecular distance in a cancer cell.

According to the study's authors, the high level of accuracy was achieved through the use of several recent technological advancements—more sophisticated microscopes and fluorescent molecules that do not flicker or produce excess glow that could be confused with other effects.

In the future, the German physicists plan to refine their method further and attempt to determine which specific macromolecules the fluorescent "ruler" will be most beneficial for.