Now, an international research team led by the Institute for Research in Biomedicine (IRB Barcelona), the University of Cambridge, UT Southwestern Medical Center and the Howard Hughes Medical Institute has unveiled a tool that promises to change how scientists study this hidden world. Called OpenCGChromatin, the software works as what the researchers describe as a computational microscope. Rather than using lenses and light, it uses computer simulations to explore how chromatin folds, how its molecular components interact with one another, and which physical forces hold its structures together. The tool is described in a study published in Nature Communications, and it has been released as open-source software so that researchers anywhere can use it to investigate the physical principles underlying genome organisation.

The central problem the team set out to solve is one of scale. Experiments can reveal individual molecular interactions in exquisite detail, or they can capture the behaviour of large stretches of chromatin in bulk, but connecting the two levels has remained stubbornly difficult. The challenge, as Dr. Modesto Orozco, head of the Molecular Modeling and Bioinformatics Laboratory at IRB Barcelona, ICREA Academia researcher and professor at the University of Barcelona, who co-led the study, explains, is to connect interactions between individual molecules with the behaviour of much larger stretches of chromatin. The new tool allows researchers to study both within the same framework, and to understand how small molecular changes can alter DNA packaging across the entire system.

Technically, OpenCGChromatin is a coarse-grained model, a class of simulation approaches that simplifies the representation of atoms and molecules while preserving the essential physics of their interactions. In this case, the tool combines a detailed representation of DNA and proteins with far greater computational efficiency than previous models could achieve. The practical consequence is striking: researchers can now study chromatin systems more than ten times larger than those accessible to earlier models at comparable resolution. That includes assemblies containing hundreds of nucleosomes, the basic units of DNA packaging, which means simulations can finally reach the scale of gene-sized structures rather than remaining confined to small fragments.

The design of the model was not developed in isolation from experimental reality. Professor Rosana Collepardo-Guevara of the University of Cambridge, who co-led the study, notes that OpenCGChromatin was inspired by beautiful cryo-electron tomography experimental work from the group of Professor Michael Rosen at UT Southwestern Medical Center and the Howard Hughes Medical Institute, who co-led the study. Cryo-electron tomography is an imaging technique that can visualise the three-dimensional organisation of biological molecules inside cells at near-atomic resolution, and grounding the model in such data helps ensure that the simulations reflect genuine biology rather than purely theoretical constructs.

A crucial test for any computational model is whether it reproduces what experiments actually show. According to the research team, the simulations generated by OpenCGChromatin reproduce observations from microscopy and biochemical experiments, providing confidence that the model captures real physical behaviour. But the simulations go a step further, revealing movements of flexible histone regions that are difficult to resolve experimentally. These histone tails, the protein segments that protrude from the nucleosome core, are known to play important roles in chromatin behaviour, yet their constant motion makes them elusive targets for laboratory imaging. The computational microscope can track them in ways that bench-top instruments cannot.

This ability to observe the unobservable is where the tool earns its microscope nickname. In the simulations, researchers can watch how nucleosomes shift position, how DNA unwraps and rewraps around histone cores, and how chemical modifications to histone proteins propagate their effects through large chromatin assemblies. David Farré-Gil, also an author of the paper, explains that the simulations help scientists understand why changing the spacing between nucleosomes, or adding chemical modifications to histones, can make chromatin behave differently. These are precisely the kinds of changes that cells use naturally to regulate gene activity, and that go awry in diseases such as cancer.

The significance of this work extends into one of the hottest areas of contemporary cell biology: biomolecular condensates. These are membrane-less compartments that form inside cells when proteins and nucleic acids cluster together, and chromatin is increasingly understood to participate in their formation and function. Collepardo-Guevara highlights that the tool now allows researchers to connect the chemical makeup of chromatin to its organisation across scales, from molecular interactions to gene-sized structures and biomolecular condensates, while remaining closely grounded in experiment. Bridging those scales within a single computational framework is what makes the approach genuinely new, rather than an incremental improvement on existing models.

The achievement behind the software is also a story of technical persistence. Collepardo-Guevara credits Kieran Russell, first author of the study, with pushing the state of the art in chromatin modelling, allowing simulations at a scale and level of molecular detail that were previously out of reach. In her view, OpenCGChromatin opens up a completely new range of questions that can now be addressed computationally. That shift matters because questions that once required years of painstaking experimental work can now be explored in silico first, generating hypotheses that experiments can then test, and allowing researchers to scan through many possible chromatin configurations far faster than laboratory methods would permit.

By releasing OpenCGChromatin as open-source software, the team has invited the wider scientific community to build on their work. Open availability means that laboratories studying gene regulation, DNA repair, genome architecture or the biophysics of condensates can adapt the model to their own questions without needing to develop the underlying technology from scratch. As chromatin research moves from describing static structures to understanding dynamic, force-driven behaviour, tools that connect molecular chemistry to large-scale genome organisation are likely to become indispensable. This computational microscope offers a way to watch the genome breathe, fold and reorganise itself, one nucleosome at a time, and to finally link the smallest molecular events to the grand architecture of our DNA.

Subject of Research: Development of a coarse-grained computational simulation tool for studying chromatin organisation and dynamics

Article Title: A new “computational microscope” to explore chromatin

Article References: A new “computational microscope” to explore chromatin. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: chromatin, nucleosome, histones, molecular dynamics simulation, coarse-grained modelling, genome organisation, OpenCGChromatin, DNA packaging, biomolecular condensates, cryo-electron tomography, computational biology, epigenetics