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Hereditary ataxias are one of the «anticipation diseases¼ types. Spinocerebral ataxia type 2 occurs when the number of CAG repeats in the coding region of the ATXN2 gene exceeds 34 or more. In healthy people, the CAG repeat region in the ATXN2 gene usually consists of 22-23 CAG trinucleotides. Mutations that increase the length of CAG repeats can cause severe neurodegenerative and neuromuscular disorders known as trinucleotide repeat expansion diseases. The mechanisms causing such diseases are associated with non-canonical configurations that can be formed in the CAG repeat region during replication, transcription or repair. This makes it relevant to study the zones of open states that arise in the region of CAG repeats under torque. The purpose of this work is to study, using mathematical modeling, zones of open states in the region of CAG repeats of the ATXN2 gene, caused by torque. It has been established that the torque effect on the 1st exon of the ATXN2 gene, in addition to the formation of open states in the promoter region, can lead to the formation of additional various sizes open states zones in the CAG repeats region. Moreover, the frequency of additional large zones genesis increases with increasing number of CAG repeats. The inverse of this frequency correlates with the dependence of the disease onset average age on the CAG repeats length. The obtained results will allow us to get closer to understanding the genetic mechanisms that cause trinucleotide repeat diseases.
RESUMO
The studies were carried out by the mathematical modeling of DNA mechanical deformations. Numerical calculations done for the interferon alpha 17 gene, which consists of 980 base pairs. It has been established that the genesis and dynamics of open states in the DNA molecule depends on the magnitude of the external influence (torque) and on the viscosity of the environment. In addition, it is shown that the dynamics of open states zones can have a jump-like character with a small change in the magnitude of the torque. When torque is applied to all 980 base pairs of the gene, the following effect is observed: an increase in the viscosity of the medium leads to an increase in the value of the torque necessary for the occurrence of OS and DNA unwinding, i.e. viscosity plays an important stabilizing role in DNA dynamics. Under the influence of a localized torque on different (by the content of A-T and G-C pairs and location) regions of the interferon alpha 17 gene, it was found that the magnitude of the external torque necessary for the occurrence of open states at all calculated values of viscosity depends on the nucleotide composition. The dependence of the torque magnitude required for the open states occurrence on viscosity is observed when the torque is applied to areas close to the gene boundaries. At the same time, the significance of the end effect, which weakens DNA, decreased with increasing viscosity of the medium.Communicated by Ramaswamy H. Sarma.
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The effect of single substitutions of protium for deuterium in hydrogen bonds between pairs of nitrogenous bases on the open states occurrence probability at high critical breaking energies of these bonds has been studied. The study was carried out using numerical methods based on the angular mathematical model of DNA. The IFNA17 gene was divided into three approximately equal parts. A comparison of the open states occurrence probability in these parts of the gene was done. To improve the accuracy of the results, a special data processing algorithm was developed. The developed methods have shown their suitability for taking into account the occurrence of open states in the entire range of high critical energies. It has been established that single 2H/1H substitutions in certain nitrogenous bases can be a mechanism for maintaining the vital activity of IFNA17 under critical conditions. In general, the developed method of the mathematical modeling provide unprecedented insight into the DNA behavior under the highest critical energy range, which greatly expands scientific understanding of nucleobases interaction.
Assuntos
Hidrogênio , Modelos Teóricos , Deutério/química , Ligação de Hidrogênio , Hidrogênio/química , Nucleotídeos , DNA/químicaRESUMO
The formation and dynamics of the open states in a double-stranded DNA molecule are largely determined by its mechanical parameters. The main one is the torque. However, the experimental study of DNA dynamics and the occurrence of open states is limited by the spatial resolution of available biophysical instruments. Therefore, in this work, on the basis of a mechanical mathematical model of DNA, calculations of the torque effect on the process of occurrence and dynamics of open states were carried out for the interferon alpha 17 gene. It was shown that torsion action leads to the occurrence of rotational movements of nitrogenous bases. This influence is nonlinear, and an increase in the amplitude of the torsion action does not lead to an automatic increase in the amplitude of rotational movements and an increase in the zones' open states. Calculations with a constant torsion moment demonstrate that open states zones are more often formed at the boundaries of the gen and in regions with a predominance of A-T pairs. It is shown, that for the occurrence of open states in the part of the gene that contains a small number of A-T pairs, a large amount of torque is required. When the torque is applied to a certain region of the gene, the probability of the formation of the open state depends on the content of A-T pairs in this region, the size of this region, and on the exposure time. For this mathematical model, open states zones can be closed when the torsion action stops. The simulation results showed that the values of the torsion moment required for the appearance of open states zones, in some cases, are close to experimentally measured (13-15 pN·nm).
Assuntos
DNA , Modelos Teóricos , DNA/genética , Movimento , TorqueRESUMO
Fluctuations in viscosity within the cell nucleus have wide limits. When a DNA molecule passes from the region of high viscosity values to the region of low values, open states, denaturation bubbles, and unweaving of DNA strands can occur. Stabilization of the molecule is provided by energy dissipation-dissipation due to interaction with the environment. Separate sections of a DNA molecule in a twisted state can experience supercoiling stress, which, among other things, is due to complex entropic effects caused by interaction with a solvent. In this work, based on the numerical solution of a mechanical mathematical model for the interferon alpha 17 gene and a fragment of the Drosophila gene, an analysis of the external environment viscosity influence on the dynamics of the DNA molecule and its stability was carried out. It has been shown that an increase in viscosity leads to a rapid stabilization of the angular vibrations of nitrogenous bases, while a decrease in viscosity changes the dynamics of DNA: the rate of change in the angular deviations of nitrogenous bases increases and the angular deformations of the DNA strands increase at each moment of time. These processes lead to DNA instability, which increases with time. Thus, the paper considers the influence of the external environment viscosity on the dissipation of the DNA nitrogenous bases' vibrational motion energy. Additionally, the study on the basis of the described model of the molecular dynamics of physiological processes at different indicators of the rheological behavior of nucleoplasm will allow a deeper understanding of the processes of nonequilibrium physics of an active substance in a living cell to be obtained.
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The sensitivity of DNA to electromagnetic radiation in different ranges differs depending on various factors. The aim of this study was to examine the molecular dynamics of DNA under the influence of external periodic influences with different frequencies. In the present paper, within the framework of a mechanical model without simplifications, we investigated the effect of various frequencies of external periodic action in the range from 1011 s-1 to 108 s-1 on the dynamics of a DNA molecule. It was shown that under the influence of an external periodic force, a DNA molecule can perform oscillatory movements with a specific frequency characteristic of this molecule, which differs from the frequency of the external influence ω. It was found that the frequency of such specific vibrations of a DNA molecule depends on the sequence of nucleotides. Using the developed mathematical model describing the rotational motion of the nitrogenous bases around the sugar-phosphate chain, it is possible to calculate the frequency and amplitude of the oscillations of an individual DNA area. Such calculations can find application in the field of molecular nanotechnology.
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DNA/química , Modelos Moleculares , MovimentoRESUMO
In the present study, the effect of 2H/1H isotopic exchange in hydrogen bonds between nitrogenous base pairs on occurrence and open states zones dynamics is investigated. These processes are studied using mathematical modeling, taking into account the number of open states between base pairs. The calculations of the probability of occurrence of open states in different parts of the gene were done depending on the localization of the deuterium atom. The mathematical modeling study demonstrated significant inequality (dependent on single 2H/1H replacement in DNA) among three parts of the gene similar in length of the frequency of occurrence of the open states. In this paper, the new convenient approach of the analysis of the abnormal frequency of open states in different parts of the gene encoding interferon alpha 17 was presented, which took into account both rising and decreasing of them that allowed to make a prediction of the functional instability of the specific DNA regions. One advantage of the new algorithm is diminishing the number of both false positive and false negative results in data filtered by this approach compared to the pure fractile methods, such as deciles or quartiles.