25 May 2015

Doshirak chromosomes

Scientists from Moscow State University assessed the benefits of DNA stacking on the principle of spaghetti

MSUA group of researchers from Lomonosov Moscow State University tried to deal with one of the least clear questions of molecular biology today – the question of how DNA strands are packed in the cell nucleus.

Scientists have come to the conclusion that laying in a special state called a "fractal globule" due to accelerated thermal diffusion allows all this genetic machinery of the cell to work with maximum speed. They published the results of their research in the May issue of the prestigious physical journal Physical Review Letters, the impact factor of which is 7.7 (Tammet al., Abnormal Diffusion in Fractal Globules).

Fractal globule is a mathematical concept. If you drop a long spinning line on the floor, it will curl up into such an unimaginably mean ball that you will either have to untangle it for hours, or run to the store for a new reel. This is an ordinary, so–called equilibrium globule. The fractal globule is a much more polite structure in this sense. In relation to the fishing line, this is a lump in which the fishing line has never tied into a knot, it just curled up many times, so that no loop around the other is entangled. Such a structure is a set of free loops of different sizes – pull it by the two ends, and it will easily unravel.


A general view of packing the chain into an equilibrium (left) and fractal (center and right) globule.
The color of the chain changes smoothly from blue at one end through green to red at the other end.

Because of this arrangement, similar to the laying of the current instant pasta "doshirak", our physicists Alexander Grosberg, Sergey Nechaev and Evgeny Shakhnovich, who first predicted it back in 1988, called such a globule "folded".

In recent years, it has been more often called fractal – and it sounds more scientific, and more fully reflects the properties of such a globule, since, as in all fractals, its structure (in this case, the shape of small and large loops) repeats on small and large scales.

For a long time this prediction remained unclaimed. But the results of research in recent years indicate that chromosomes (DNA strands) are formed in the nucleus in exactly this configuration – in a fractal globule. Today there is no consensus on this in the scientific community, but most specialists working in this field are very intrigued, and over the past 5-7 years there has been a whole stream of research on the genome folded into a fractal globule.

Intuitively, it was understandable. The double helix of DNA, reinforced with a corresponding set of proteins, is a long strand called chromatin. And if this chromatin is a library of technical manuals on the synthesis of a particular protein needed by the body, then it would be better not to touch the text of these manuals unnecessarily and, accordingly, avoid unnecessary crossings of one gene with another, fold the chromatin thread so that parts of this thread are not tied together in a knot in any place. Therefore, no matter how this chromatin thread in the nucleus develops, it should not repeat the fate of a fishing line that accidentally fell to the floor, that is, it should not be a simple globule, but a fractal one.

In addition, a thread in a fractal globule that does not have nodes, in theory, should have a higher freedom of movement, which is important for DNA. In order for DNA to function normally, it is necessary that its individual parts meet with each other at the right moment, "including" the signal for reading and indicating to the whole system the place from where this reading should begin, and all this should happen quickly enough.

"According to current theories, in a polymer chain folded into an ordinary globule, the average square of the thermal displacement of a particle (in this case, the link of this chain) increases proportionally to time to the degree of 0.25," said Mikhail Tamm, senior researcher at the Department of Polymer and Crystal Physics at the Faculty of Physics of Moscow State University, who is one of the authors of the study.

According to Mikhail Tamm, he and his colleagues managed to come up with a somewhat similar theory for a link of a polymer chain folded into a fractal globule.

"We were able to assess the thermal dynamics inherent in this type of laying. Our computer simulation has well confirmed the theoretical result," Mikhail Tamm noted.

Scientists from Moscow State University created their own computer modeling method, which allowed to stack the chromatin chain into a fractal globule and track the thermal processes taking place there. They managed to do what their predecessors had failed to do – simulate the situation with a long chain consisting of a quarter of a million links.

According to Mikhail Tamm, modeling of long chains, namely they allow to obtain any significant results, is complicated by the fact that they take a very long time to reach an equilibrium state, at which it is already possible to investigate the thermal diffusion occurring there.

Having successfully solved this problem due to a well-built program and a lot of computer time on the Lomonosov Moscow State University supercomputer, the researchers were able to assess the dynamics of thermal motion in a fractal globule. It turned out that the particles – that is, the links of the chromatin chain – move faster than in a conventional, non-fractal, globule. Here, the average square of the thermal displacement of the chromatin chain link grew proportionally to time, not to the degree of 0.25, as in a conventional globule, but to the degree of 0.4, that is, the movement of the links there turned out to be much faster. This, apparently, among other things, determined the choice of a fractal globule for the chromatin filament as a method of its laying in the nucleus.

The researchers hope that their work will allow them to better understand exactly how all the machinery related to storing and reading information in DNA functions.

"From the point of view of dynamics, we would like to understand what characteristic times are embedded there, what processes can occur simply due to thermal motion, and what inevitably requires the involvement of active elements that accelerate the work of DNA," Mikhail Tamm summed up.

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