Nearly every cell in the human body contains essentially the same genetic information, yet different cells activate different genes. For regulatory proteins to reach these genes, DNA must be accessible. This accessibility depends not only on the genetic code itself but also on DNA’s physical properties – its shape, flexibility, and ability to interact with proteins.
Researchers are exploring what is known as DNA’s physical code – the molecule’s physical properties, which may influence how cells use the genetic information encoded within DNA. An international team of researchers, including Dr Daiva Petkevičiūtė-Gerlach from Kaunas University of Technology (KTU), investigated this code on an unprecedented scale by performing atomistic simulations and analyses of the shape, flexibility, and dynamics of a large set of DNA sequences.
Not Only Genetic Information, But DNA Shape Matters
“Most of us know that DNA is a long, thin molecule in which the genetic information of all living organisms is encoded in a sequence of four nucleotides – adenine (A), thymine (T), guanine (G) and cytosine (C),” says Dr Daiva Petkevičiūtė-Gerlach, a researcher at KTU’s Faculty of Mathematics and Natural Sciences.
She explains that the sequence of nucleotides determines not only the information stored in DNA, but also the molecule’s shape, flexibility and ability to move. As a result, two different DNA segments may differ not only in the genetic information they contain, but also in the way they bend, deform or interact with other molecules within the cell.
“The physical properties of DNA, which depend on its nucleotide sequence, influence how it interacts with proteins and therefore play an important role in gene expression. For example, proteins that regulate gene activity recognise not only the specific nucleotide sequence when binding to DNA, but also its three-dimensional structure, shape and flexibility,” explains Dr Petkevičiūtė-Gerlach.
This is particularly important because DNA is not freely extended within the cell. To fit the long molecule into the small cell nucleus, DNA wraps around histone protein complexes to form nucleosomes. This arrangement allows the genetic material to be compactly packed, but at the same time it can restrict access to certain regions of the DNA.
If a particular DNA region bends or rearranges more easily, it may be more accessible to cellular proteins. Conversely, stiffer or more tightly packed regions may remain harder to access. As a result, the mechanical properties of DNA may play an important role in regulating gene expression – the process that determines which genes are active at any given time and which remain switched off.
However, determining how different nucleotide sequences alter the physical properties of DNA is far from straightforward. Understanding these relationships requires far more than studying a handful of individual DNA fragments – it demands the comparison of a vast number of different sequences.
DNA Modelling on an Unprecedented Scale
The longer the DNA segment being studied, the greater the number of possible sequence combinations. For example, there are as many as 4,096 possible sequences consisting of just six nucleotides. As part of the international HexABC project, researchers incorporated all of these combinations into 190 longer DNA fragments and investigated them using molecular dynamics simulations.
This method simulates the movement and interactions of every atom in the DNA molecule and the surrounding solution. It enables researchers to observe how different DNA segments vibrate, bend and change their shape.
“There are various methods for modelling DNA. Simpler models can analyse millions of DNA sequences in a single day, but they are not as detailed. In this study, we chose one of the most sophisticated atomistic modelling approaches available. As a result, the calculations were significantly slower and required enormous computational resources,” emphasises Dr Petkevičiūtė-Gerlach.
The simulations ran on hundreds of computers across Europe and the United States over several months. Integrating and analysing the resulting data took more than a year, reflecting both the scale of the simulations and the size of the dataset.
According to Dr Petkevičiūtė-Gerlach, one of the study’s most important achievements was that experts across the field agreed on a common modelling methodology and created a large, publicly accessible dataset that other researchers will be able to use in the future.
The study of these DNA molecules relied entirely on mathematical calculations. Mathematical methods made it possible to describe the molecule’s geometry and movement, analyse the vast amount of data generated during the simulations, and compare the physical properties of different DNA sequences.
One of the most interesting findings emerged when the simulation data were compared with the genomes of humans and many other species. The researchers found that, over the course of evolution, mutations that caused the smallest changes to DNA’s physical properties were more likely to be preserved. In other words, evolution appears to favour not only the preservation of genetic information, but also the mechanical stability of the DNA molecule.
Although this research focused on advancing the fundamental understanding of DNA’s physical properties, molecular dynamics simulations are also widely used in practice. They are one of the principal tools employed during the theoretical phase of drug discovery in pharmaceutical companies.
According to Dr Petkevičiūtė-Gerlach, many researchers, including herself, seek to understand how the mechanical properties of DNA contribute to the development of certain diseases. In the future, this study is expected to advance the entire field of DNA modelling, supporting not only molecular dynamics simulations but also the development of other modelling approaches and methods.
“DNA is an extraordinarily fascinating molecule. The more we learn about its structure, physical properties and their relationship with genetic information, the better we understand the processes of life and the better equipped we are to develop new solutions in medicine, biotechnology and artificial intelligence applications in biology,” concludes Dr Petkevičiūtė-Gerlach.
The article “hexABC: Seeking the Physical Code of DNA” is available here.
