DNA Strands Guide Proteins into Precise Crystals

For decades, scientists have relied on painstaking trial and error to coax proteins into crystalline forms, a step that enables researchers to determine protein structures and inform drug design, enzyme engineering and disease research. Northwestern University chemists have now developed an approach that replaces that unpredictable process with intentional design, using flexible DNA strands as both a blueprint and a programmable molecular glue. 

In the new study, published in Science Advances, the Northwestern team directed proteins to assemble into diffraction-quality crystal structures with atomic-level order. The strategy allowed precise control over how proteins connect, producing unusually soft, flexible crystals while still achieving the structural order needed to determine protein structures. The work challenges a long-held assumption that flexible building blocks cannot form crystals with atomic-level order, and it could enable a new generation of customizable biomaterials for biosensing, drug delivery, bioelectronics and robotics.

“The implications of this research are profound,” said Chad A. Mirkin, the study leader. “Proteins are the building blocks of life, and their structure determines their function. When we intentionally determine those structures, we gain powerful new insights into how proteins recognize other molecules, catalyze chemical reactions and interact with living systems.”

X-ray crystallography remains the standard method for revealing protein structures, but persuading proteins to form suitable crystals is often one of the most unreliable steps. To address this, Mirkin’s team attached short DNA strands to individual proteins, allowing complementary strands to pull neighboring proteins together into precisely designed crystals. The researchers varied factors such as DNA strand length and placement to study how each affected crystal formation, then used X-ray crystallography to examine the results.

“The well-defined DNA-DNA interactions drove the assembly and crystallization process,” said Zhenyu Han, the paper's first author. “"As a result, the proteins not only adopted specific positions and orientations, but the atoms within each protein are also aligned in the exact same way throughout the crystal.”

To validate the method, the team grew more than 1,000 protein crystals and determined atomic structures for 28 distinct protein-DNA designs, with consistent results across variations in DNA length and position. “These numbers show that we didn’t just get lucky,” Mirkin said. “We systematically demonstrated this approach across literally hundreds of possibilities and showed over and over again that it’s a reliable method.”