DNA motifs
Non-standard DNA structures will become nanocontainers for medicines
Employees of the Federal Scientific and Clinical Center (FNCC) of Physico-Chemical Medicine have studied the ability of DNA molecules to form unusual structures – i-motifs. They are characteristic of some fragments of DNA and RNA and are four-stranded cross-shaped structures. These designs can be sensors and nanocontainers that release stored substances under certain conditions, which is useful, for example, when delivering medicines. The work was carried out with the support of the grant Published in the journal Physical Chemistry Chemical Physics (Protopopova et al., The structural diversity of C-rich DNA aggregates: unusual self-assembly of beetle-like nanostructures), the RNF press release briefly reports about it.
In recent years, there have been works describing very unusual, so-called non-canonical structures of DNA molecules. For example, fragments of a helix containing a large number of one type of its nucleotide parts (cytidine, C) – C-rich fragments of DNA or RNA – form a four-stranded structure of i-motifs. According to scientists, it is easier to explain their structure on the fingers, and literally. First, connect the ends of the fingers of both hands. This is how bonds are formed between two nucleotide chains in ordinary DNA. Now ask a friend to do the same, but first by sticking his fingers between yours. The result was an i-motif, or rather, its core. Such structures can be formed in a system of one, two, three and four separate DNA molecules.
In order to understand the patterns of assembly of multidimensional i-motifs, scientists investigated the behavior of DNA molecules consisting of cytidine blocks (C-block) and inert fragments, that is, not involved in the formation of the i-motif. The formation and variety of assemblies can be especially clearly observed using atomic force microscopy, which allows you to determine the surface relief with very high resolution, up to atomic. It turned out that C-blocks form a dense ordered structure, while the number of tails formed in them allows us to judge the number of nucleotide chains in the structure. In general, the structures resemble "bugs" or "caterpillars": the i-motif forms a "body", and the inert fragments bulge out in the form of "legs".
"Today it is clear that the change in the spatial organization of chromatin plays an important regulatory role. The development of 3D genomics, the study of adaptive mechanisms and the nature of pathologies associated with genomic rearrangements – oncology, neurodegenerative diseases and others – require an understanding of the dynamics of DNA structures. Recent research data suggest that the ability of the same nucleotide fragments to form different structures and participate in the self-assembly of complexes with other molecules is a natural function of DNA and RNA. Therefore, it is very important to investigate the patterns of structural transitions, to find out exactly how and why unusual structures are formed," says Galina Pozmogova, Doctor of Chemical Sciences, Professor, head of the Laboratory of Artificial Antibody Genesis of the FNCC of Physico-Chemical Medicine.
Scientists have constructed small nucleotide chains from cytidine (the core of the i-motif, or "body of bugs") and thymidine inert to the i-motif ("legs of bugs"). Using an arsenal of physico-chemical methods, they found out that, depending on the length of the C-block and the assembly conditions, it is possible to obtain complexes with a different number of "legs". In addition, the researchers proposed a fundamental principle of assembling nucleotide chains into similar structures. Long C-sections of different molecules are stacked so as to form a single core of the i-motif with a minimum number of loops for each nucleotide chain. Computer modeling has shown that such behavior of molecules is energetically advantageous, and therefore the resulting structure is stable.
"Using the example of new assemblies, we have shown that we can find the rules by which branched nanoconstructions are formed, which are especially in demand when creating three-dimensional DNA origami models. The significance of our results is twofold. On the one hand, they are interesting from the point of view of the biological function of i-motives – the regulation of processes involving DNA. On the other hand, they are important for the development and creation of nanostructures with specified adjustable parameters. We have this number of "legs", to the ends of which some functional chemical groups can be attached. And in order to regulate another important parameter of the stability of i-motional structures – pH-dependent shape change, we proposed to introduce special chemically modified links into the composition of the initial nucleotide chains, which expands the possibilities of their use in living systems," concludes Galina Pozmogova.
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