Science & Technology

Meet Yale’s maestro of MicroED

A new technology upgrade brings microcrystal electron diffraction — which helps determine the atomic structure of small crystals — to the Yale campus.

5 min read
Brandon Mercado

Brandon Mercado

Portrait by Harold Shapiro

Meet Yale’s maestro of MicroED
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For a crystal-clear view of cutting-edge science, step into Brandon Mercado’s lab in the basement of Kline Chemistry Laboratory.

This suite of rooms, collectively called the Yale Chemical and Biophysical Instrumentation Center (CBIC), is filled with all manner of spectrometers, a fluorimeter, several X-ray devices, and a computed tomography (CT) scanner. This impressive assemblage of tech enables Yale researchers to gain valuable insights into the makeup of chemical and biophysical samples for new discoveries in chemistry, medicine, and other disciplines.

But there’s a new kid in town.

CBIC’s Structural Science Facility now houses a state-of-the-art microcrystal electron diffractometer — a game-changing instrument that reveals structural details of materials down to the atomic level. The technology represents a major boost in Yale’s ability to characterize the structure of small molecules and proteins.

And it is in no small part due to Mercado, the Structural Science Facility’s director who recently received a Linda K. Lorimer Award for his advocacy for Yale’s investment in MicroED.

Yale News caught up with Mercado as he and other university leaders celebrated the CBIC upgrade with a ribbon cutting ceremony Jan. 9. The interview has been edited and condensed.

For those who aren’t familiar with it, what is MicroED?

Brandon Mercado: MicroED, or microcrystal electron diffraction, is a cutting-edge technique that uses electron diffraction to determine the atomic structure of small crystals. Unlike traditional X-ray crystallography, which requires larger crystals, MicroED can work with crystals that are just nanometers in size. This opens doors to structural analysis in cases where growing large crystals is challenging or impossible. This is particularly valuable in structural biology, chemistry, and materials science.

A reconstruction of the atomic arrangement of compounds with a microcrystal.

A reconstruction of the atomic arrangement of compounds with a microcrystal.

Image courtesy of Brandon Mercado

How does an electron diffractometer work?

Mercado: It uses a beam of highly accelerated electrons to interact with a crystal sample. As the electrons pass through the rotating crystal, it produces a 3D diffraction pattern based on the atomic structure of the material. These patterns are then recorded and processed to determine the atomic arrangement of the crystal. The high sensitivity of electrons to atomic nuclei means the technique is extremely efficient, requiring crystalline grains that cannot be seen with the naked eye or even a traditional light microscope.

What are some of the applications for this technology?

Mercado: MicroED has wide-ranging applications across numerous scientific disciplines. In structural biology, it has been used to model challenging protein and peptide targets, including membrane proteins and amyloid fibrils. Pharmaceutical chemists have used MicroED to determine the chirality — or handedness — of small molecules and drug candidates, a result previously thought to require X-rays. Recent advancements have shown that electrons can be just as reliable, opening new avenues for drug development.

In materials science, MicroED is ideally suited for analyzing inherently nanoscale materials such as zeolites, metal-organic frameworks (MOFs), and polymers.

Finally, chemists have applied MicroED to resolve the structures of natural products and catalysts. At Yale’s Structural Science Facility, which is within the CBIC, we’ve determined the structures of a microcrystalline MOF, a rhenium catalyst, and a natural product derived from total synthesis, leveraging both internal and external MicroED resources.

What drew you to MicroED? Do you remember the first time you used it?

Mercado: The Structural Science Facility often encounters researchers who bring in what might be the world’s only supply of a material with the potential to make a massive impact in their field. However, these materials are often in exceedingly small quantities, and their individual crystalline grains are too small for traditional X-ray diffraction. These samples are typically turned away, requiring researchers to invest significant additional effort in producing or isolating more material and growing larger crystals.

After several high-profile papers on MicroED were published in late 2018, I immediately recognized its potential to overcome those limitations. To explore this new technique, I traveled to UCLA to learn in the labs of the corresponding authors of one such report. We worked on a natural product isolated in the lab of Seth Herzon at Yale. Seeing that first diffraction pattern was absolutely thrilling!

It took a couple more years before we achieved data quality sufficient for structure determination, but the results were worth the wait. The project culminated in a published structure revision of a compound whose structure had been misassigned for nearly 20 years.

What was involved in bringing this technology to Yale?

Mercado: Establishing MicroED as a resource in the Structural Science Facility was a long and complex journey that required a combination of vision, collaboration, and logistics.

The process began with identifying the growing demand for MicroED capabilities, particularly as a solution to the classic challenge of having too little material or crystals too small for X-ray diffraction. I advocated for the necessary investment at both the federal level and through Yale’s recently established internal funding mechanism for core equipment.

We allocated center and institutional funds to renovate the infrastructure to accommodate this new capability. Meanwhile, the timing was fortuitous — several vendors were developing off-the-shelf solutions for MicroED. With secured funding, we purchased their turn-key solution, making it only the second installation of such a resource at a university in the Americas.

Now that MicroED is up and running at Yale, what new things are you learning?

Mercado: Although we’ve only been operational for a little over a month, the system has already exceeded my expectations. During the application training, we tested a crystalline material and successfully determined a new structure related to the total synthesis of securamines, which are bioactive anticancer targets. I hadn’t anticipated being able to deliver a high-value result so quickly, and this early success validated our efforts to establish MicroED at Yale.

What’s most exciting is how versatile and robust MicroED has proven to be. Its adaptability to a wide range of sample types and experimental conditions has surpassed what I initially envisioned. These early results confirm that MicroED will continue to drive impactful discoveries derived entirely from internal expertise and resources.