UTHealth Houston study reveals DNA’s hidden physical language
DNA has long been viewed as life’s instruction manual, with its sequence of genetic letters directing everything from growth to disease. But new research suggests those letters tell only part of the story.
New research from Matthew Baker, PhD, assistant professor in the Department of Biochemistry and Molecular Biology at McGovern Medical School at UTHealth Houston, suggests that the physical shape of DNA may contain its own hidden language that helps determine how proteins recognize and interact with the genome.
“Most people think of DNA as a sequence of genetic letters that stores biological information,” Baker said. “However, DNA is also a physical molecule that bends, twists, stretches, and coils into complex three-dimensional shapes.”
The study (external link) explores how the structure and mechanical properties of DNA help determine how proteins recognize and interact with it. The findings provide new insight into one of biology’s most fundamental processes and suggest that DNA’s three-dimensional architecture is just as important as its genetic sequence.
Using a combination of structural biology, computational modeling, and biophysical analysis, the research team investigated how the bacterial enzyme DNA gyrase interacts with negatively supercoiled DNA. The project built upon a previously determined cryo-electron microscopy structure developed by collaborators Lynn Zechiedrich, PhD, and Valerie Lamour, PhD, which captured DNA gyrase bound to a supercoiled DNA minicircle.
While researchers could accurately model the protein, the DNA itself presented a significant challenge. Existing computational tools were designed primarily for the standard form of DNA and struggled to interpret the highly bent and twisted structures found in the complex.
To overcome that limitation, the team developed new computational approaches that analyzed the DNA directly from cryo-electron microscopy data. By identifying characteristic patterns within the experimental images, the researchers reconstructed a far more complete model of the DNA, including regions that adopted unusual structural conformations while interacting with DNA gyrase.
Once the DNA could be modeled with confidence, the researchers examined its flexibility, bending, groove geometry, and other structural features. Their analysis revealed that DNA gyrase does not rely solely on genetic sequence when recognizing DNA.
“We found that DNA gyrase preferentially recognizes and cleaves DNA at sites defined by their mechanical properties rather than by sequence alone,” Baker said.
The researchers identified a distinctive deformability pattern in which relatively rigid and highly flexible regions of DNA converge, creating an environment favored by the enzyme. The findings suggest that DNA mechanics represent an additional layer of biological information that helps guide protein-DNA interactions.
“Our findings suggest that DNA contains multiple layers of information, with both sequence and structure contributing to biological function,” Baker said.
The implications extend well beyond DNA gyrase. DNA structure and topology influence nearly every aspect of genome function, including chromosome organization, gene regulation, DNA replication, repair, and nucleosome positioning. Understanding how proteins recognize these mechanical features could provide scientists with a new framework for studying how genomes function across many biological systems.
“One of the most exciting outcomes of this work is the emerging realization that DNA may encode information through its physical properties in addition to its nucleotide sequence,” Baker said. “Our studies suggest that proteins can recognize characteristic mechanical signatures within DNA, including patterns of flexibility, rigidity, and deformation.”
Building on these findings, the research team has already applied the same analytical framework to another DNA-processing enzyme, topoisomerase VI, in research recently published in Nature Communications. That work revealed similar deformability patterns, suggesting that DNA mechanics may play a broader role in directing protein-DNA interactions than previously appreciated.
Moving forward, the researchers plan to apply their integrated structural, computational, and biochemical pipeline to additional DNA-binding proteins. By combining cryo-electron microscopy with quantitative analyses of DNA deformability and topology, they hope to determine how broadly DNA mechanics contributes to protein recognition and biological function.
“By developing experimental and computational approaches that directly measure and model these properties, we hope to establish a predictive framework for understanding how DNA structure and mechanics contribute to genome organization and regulation across diverse biological systems,” Baker said.