AI and Advanced Microscopy Unveil Complex DNA Structures with Nanometer Precision

Under or over? Automated technique can visualize and measure DNA tangles

At school, it's often presented as a tidy double helix but scientists are revealing the varied and intricate shapes of DNA molecules. DNA is a molecule found in just about every living cell. Because the molecule is long, it ends up twisting on itself and getting tangled. Enzymes in the body try to regulate this process but when that fails, normal activity in the cell can be disrupted, which triggers ill health and could be a factor in diseases such as cancer and neurodegeneration. To find cures for major illnesses, scientists need to understand the complex shape of DNA tangles. Existing lab techniques enable them to plot the shape and structure of DNA tangles, but it is laborious and time-consuming. An international scientific team led by the University of Sheffield in the UK has now automated the process. Using what is known as an atomic force microscope, advanced computer software and AI, they are able to visualize the DNA molecules, trace their paths and measure them. The paper, "Quantifying complexity in DNA structures with high resolution Atomic Force Microscopy," is published in the journal Nature Communications. Understanding the way DNA changes shape, a field of science known as DNA topology, requires researchers to conduct analysis at the nanoscale, where a nanometer is one billionth of a meter. Alice Pyne, Professor of Biophysics at the University of Sheffield, who supervised the research, said, "This is the first time we have been able to determine the structure of individual complex DNA structures found in cells with nanometer precision. We have done that by developing advanced new image analysis tools that can do in a matter of seconds that before may have taken hours. "This will allow us to look at what complex structures may be formed in the cell during normal and abnormal cellular processes, such as DNA replication, and understand their implications. From here, we can start to look at how these complex topologies and structures affect proteins interacting with the genome, for example, key antibiotic and anti-cancer targets such as topoisomerases (an enzyme that untangles knotted DNA)." Dr. Sean Colloms, from the School of Molecular Bioscience at the University of Glasgow and a co-author of the study, said, "DNA is a really long molecule. Just like any long piece of string, the DNA in our cells gets tangled and knotted. If we want to study the processes in cells that lead to DNA knotting, as well as the action of topoisomerases to remove the knotting, we need to be able to determine exactly how the DNA is tangled. "At each DNA crossing, we can see which piece of DNA goes over which and this even allows us to tell the difference between one knot and its mirror image, which is important in our studies." An atomic force microscope uses a tiny probe to physically measure the object under analysis -- rather than light or electrons as in other types of microscope. That difference makes it suitable for nanoscale analysis. "Molecular simulations help us understand how DNA interacts with mica surfaces in AFM experiments," said Dušan Račko from the Polymer Institute of the Slovak Academy of Sciences, who was involved in the study. "By developing advanced models, we can generate thousands of molecular structures to train future AI frameworks -- bringing us closer to visualizing and understanding topology of complex DNA assemblies." The study is the culmination of an international research collaboration involving scientists from six universities and research institutes from across the UK, Slovakia and France.

AI and advanced microscopy reveal tangled DNA structures with nanometer precision

University of SheffieldAug 22 2025 At school, it's often presented as a tidy double helix but scientists are revealing the varied and intricate shapes of DNA molecules. DNA is a molecule found in just about every living cell. Because the molecule is long, it ends up twisting on itself and getting tangled. Enzymes in the body try to regulate this process but when that fails, normal activity in the cell can be disrupted, which triggers ill health and could be a factor in diseases such as cancer and neurodegeneration. To find cures for major illnesses, scientists need to understand the complex shape of DNA tangles. Existing lab techniques enable them to plot the shape and structure of DNA tangles but it is laborious and time-consuming. An international scientific team led by the University of Sheffield in the UK has now automated the process. Using what is known as an atomic force microscope, advanced computer software and AI - they are able to visualize the DNA molecules, trace their paths and measure them. Understanding the way DNA changes shape, a field of science known as DNA topology, requires researchers to conduct analysis at the nanoscale, where a nanometre is one billionth of a metre. Alice Pyne, Professor of Biophysics at the University of Sheffield, who supervised the research, said: "This is the first time we have been able to determine the structure of individual complex DNA structures found in cells with nanometre precision. We have done that by developing advanced new image analysis tools that can do in a matter of seconds that before may have taken hours. "This will allow us to look at what complex structures may be formed in the cell during normal and abnormal cellular processes, such as DNA replication and understand their implications. From here, we can start to look at how these complex topologies and structures affect proteins interacting with the genome, for example key antibiotic and anti-cancer targets such as topoisomerases (an enzyme that untangles knotted DNA)." Dr Sean Colloms, from the School of Molecular Bioscience at the University of Glasgow and a co-author of the study, said: "DNA is a really long molecule. Just like any long piece of string, the DNA in our cells gets tangled and knotted. If we want to study the processes in cells that lead to DNA knotting, as well as the action of topoisomerases to remove the knotting, we need to be able to determine exactly how the DNA is tangled. "At each DNA crossing, we can see which piece of DNA goes over which and this even allows us to tell the difference between one knot and its mirror image, which is important in our studies." An atomic force microscope uses a tiny probe to physically measure the object under analysis - rather than light or electrons as in other types of microscope. That difference makes it suitable for nanoscale analysis. "Molecular simulations help us understand how DNA interacts with mica surfaces in AFM experiments," said Dušan Račko from the Polymer Institute of the Slovak Academy of Sciences, who was involved in the study. "By developing advanced models, we can generate thousands of molecular structures to train future AI frameworks - bringing us closer to visualizing and understanding topology of complex DNA assemblies." The study is the culmination of an international research collaboration involving scientists from 6 universities and research institutes from across the UK, Slovakia and France. University of Sheffield Journal reference: Holmes, E. P., et al. (2025). Quantifying complexity in DNA structures with high resolution Atomic Force Microscopy. Nature Communications. doi.org/10.1038/s41467-025-60559-x.