Tag Archives: conformational analysis

Energetic, conformational and electron density topological properties of 2′,3′-didehydro-2′,3′-dideoxythymidine: a quantum chemical study

A. G. Ponomareva, Ye. P. Yurenko, R. O. Zhurakivsky

Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv;
e-mail: a.g.ponomareva@gmail.com; yevgen.yurenko@gmail.com; roman@zhr.org.ua

Comprehensive conformational analysis of 2′,3′-didehydro-2′,3′-dideoxythymidine (d4T), also known as anti-AIDS drug stavudine, has been performed for the first time at the MP2/6-311++G(d,p)//DFT B3LYP/6-31++G(d,p) level of the theory. It was established that d4T energy landscape contained 19 local minima, which corresponded to stable conformers. Eight types of specific intramolecular interactions, which govern the d4T conformational properties, were identified, namely: O5′H∙∙∙O2, C1′H′∙∙∙O2, C6H∙∙∙O5′, C6H∙∙∙O4′, C5′H1′∙∙∙O2, C5′H2′∙∙∙O2, C6H∙∙∙H1′C5′, C2′∙∙∙O2. The obtained results confirm the actual point of view that d4T biological activity is, most likely, connected with termination of the DNA chain synthesis in the 5′-3′ direction. Thus, d4T competes with canonical thymidine in binding an active site of HIV-1 reverse transcriptase.

The 5′-deoxyadenylic acid molecule conformational capacity: quantum-mechanical investigation using density functional theory (DFT)

T. Yu. Nikolaienko1, L. A. Bulavin1, D. M. Hovorun1,2

1Taras Shevchenko Kyiv National University, Ukraine;
2Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv;
е-mail: tim_mail@ukr.net

Exhaustive conformational analysis of the 5′-deoxyadenylic acid molecule, has been carried out by the quantum-mechanical density functional theory method at the MP2/6-311++G(d,p) // DFT B3LYP/6-31G(d,p) theory level. As many as 726 of its conformations have been revealed with the relative gas phase Gibbs energies under standard­ conditions from 0 to 12.1 kcal/mole. It has been shown, that the energetically most favorable conformation has north sugar puckering and syn- orien­tation of the nitrogenous base and is stabilized by intramolecular OP1HP1∙∙∙N3 and O3′H∙∙∙OP hydrogen bonds. Four conformations have been shown to have their geometry similar to that of AI-DNA and four – of BI-DNA. One conformer of the 5′-deoxyadenylic acid molecule is similar to its sodium salt hexahydrate structure in crystalline state resolved by the X-ray diffraction method and taken from literature. It is shown that effective charges of C4′ and C5′ atoms are the most sensitive to the molecule conformation ones. The role of the intramolecular OH∙∙∙N hydrogen bonds in formation of the 5′-deoxyadenylic acid molecule structure has been demonstrated.

Conformational capacity of 2′,3′-didehydro-2′,3′-dideoxyadenosine as a key to understanding its biological activity: results of quantum chemical modelling


A. G. Ponomareva1, Ye. P. Yurenko1, R. O. Zhurakivsky1, D. M. Hovorun1,2

1Institute of Molecular Biology and Genetics, National Academy
of Sciences of Ukraine, Kyiv;
e-mail: yevgen.yurenko@gmail.com;
2Institute of High Technologies, Taras Shevchenko Kyiv
National University, Ukraine

Comprehensive conformational analysis of the biologically active nucleoside 2′,3′-didehydro-2′,3′-dideoxyadenosine (d4A) has been performed at the MP2/6-311++G(d,p)//DFT B3LYP/6-31G(d,p) level of theory. The energetic, geometrical and polar characteristics of twenty one d4A conformers as well as their conformational equilibrium were investigated. The electron density topological analysis allowed us to establish that the d4A molecule is stabilized by eight types of intramolecular interactions: O5′H…N3, O5′H…C8, C8H…O5′, C2′H…N3, C5′H1…N3, C5′H2…N3 та C8H…H1/2C5′. The obtained results of conformational analysis lead us to think that d4A may be a terminator of the DNA chain sythesis in the 5′-3′ direction. Thus it can be inferred that d4A competes with canonical 2′-deoxyadenosine in binding an active site of the corresponding enzyme.

Conformational variety and physical properties of the 1,2-dideoxyribofuranose-5-phosphate, the model DNA monomer structural unit

T. Yu. Nikolaienko1, L. A. Bulavin1, D. M. Hovorun1,2, O. O. Missura1

1Taras Shevchenko Kyiv National University, Ukraine;
2Institute of Molecular Biology and Genetics,
National Academy of Sciences of Ukraine, Kyiv;
e-mail: tim_mail@ukr.net

The results of exhaustive quantum-mechani­cal conformational analysis of 1,2-dideoxyribofuranose-5-phosphate molecule, the model DNA backbone structural unit, are presented. As many as 282 conformations with the relative Gibbs energies from 0 to 8.9 kcal/mole have been obtained at the MP2/cc-pVTZ // DFT B3LYP/cc-pVTZ theory level. Among them seven structures are similar to those of the DNA backbone in its AI, BI and ZII forms, while the B-DNA-like conformation has the lowest Gibbs energy (ΔG = 3.3 kcal/mole). It is shown that the relaxed force constants values­ for conformational parameters of all DNA-like conformations satisfy inequality Kγ > Kα′ > Kε > Kβ.

The effect of chlorination of nucleotide bases on the conformational properties of thymidine monophosphate

T. M. Mukhina, T. Yu. Nikolaienko

Taras Shevchenko National University of Kyiv, Ukraine;
e-mail: MukhinaTanyaM@gmail.com; tim_mail@ukr.net

Recent studies on Escherichia coli bacteria cultivation, in which DNA thymine was replaced with 5-chlorouracil have refreshed the problem of understanding the changes to physical properties of DNA monomers resultant from chemical modifications. These studies have shown that the replacement did not affect the normal activities and division of the bacteria, but has significantly reduced its life span. In this paper a comparative analysis was carried out by the methods of computational experiment of a set of 687 possible conformers of natural monomeric DNA unit (2′-deoxyribonucleotide thymidine monophosphate) and 660 conformers of 5-chloro-2′-deoxyuridine monophosphate – a similar molecules in which the natural nitrogenous base thymine is substituted with 5-chlorouracil. Structures of stable conformers of the modified deoxyribonucleotide have been obtained and physical factors, which determine their variation from the conformers of the unmodified molecule have been analyzed. A comparative analysis of the elastic properties of conformers­ of investigated molecules and non-covalent interactions present in them was conducted. The results can be used for planning experiments on synthesis of artificial DNA suitable for incorporation into living organisms.