High-speed protein films to aid in drug design

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Microscopic crystals grown in droplets during the process of crystallography. Credit: University of Southampton


Microscopic crystals grown in droplets during the process of crystallography. Credit: University of Southampton

Researchers from the University of Southampton have developed technology to help scientists observe proteins in motion. Understanding how proteins move will allow new drugs to be designed.

X-ray crystallography is a scientific method that produces a 3D view of molecules with fine atomic-level detail. It has been used to determine the structure of many thousands of proteins—nature’s molecular machines.

The new challenge for scientists is to use X-ray crystallography to create “movies” of proteins in action. This is extremely difficult, with only a small part made. Efforts are hampered by the blurring of protein structure during the capture of each frame on film.

Now, a team from the Institute for Life Sciences at the University of Southampton, working in collaboration with Diamond Light Source and Douglas Instruments, have tackled this challenge by miniaturizing protein crystals and developing a method for rapid mixing. Their findings are published in the journal IUCrJ.

Nucleus and rapid growth of lysozyme. Credit: IUCrJ (2024). DOI: 10.1107/S2052252524001799

The first author, Jack Stubbs, explains how crystals are analyzed. “Protein crystals are scattered, one by one, in an intense X-ray beam to capture pictures of the crystals from every possible angle. The resulting scattered X-ray patterns are used to decipher the protein’s structure.

“The method can also be used to capture 3D pictures of proteins at different time points. Stitch them together and you effectively have a movie of the proteins in action, which provides clues about their function.”

During this process, it is important that the X-ray “pictures” capture the proteins in the same shape, at the same moment in time, to avoid “blurring” their structure. This is the problem that the team has faced.

Droplet coalescence by surfactant exchange to destabilize the interface. Credit: IUCrJ (2024). DOI: 10.1107/S2052252524001799

Researchers have developed a “microfluidic droplet method” to produce millions of droplets – each of which acts as a miniature test tube, the size of one trillionth of a liter, for proteins to crystallize. In such extremely small volumes, the small amount of protein available means that the crystals can only grow to a few microns in length – roughly the same size as a bacterium.

Dots also have a special blending ability. As a droplet moves, the contents circulate, much like mixing, to promote rapid mixing. The team demonstrated mixing times approaching 1 millisecond, 1/1000 of a second. This sets a new standard for time-resolved crystallography.

The main scientist, Dr. Jonathan West, stated: “Our research marks a significant advance for time-resolved serial crystallography. The ability to engineer microcrystal size and initiate reactions with rapid mixing opens up exciting opportunities to understand the structural dynamics of proteins with millisecond precision .”

The implications of this research extend beyond the laboratory. By sharing these latest methods with crystallography scientists, the researchers aim to greatly expand our understanding of how proteins move, how movement lends itself to function, and how drugs can alter movement.

More information:
Jack Stubbs et al, Droplet Microfluidics for Time-Resolved Serial Crystallography, IUCrJ (2024). DOI: 10.1107/S2052252524001799

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