Investigation of solvent effect and NMR shielding tensors of p53 tumor-suppressor gene in drug design (original) (raw)
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Investigation of Solvent Effect on CUA Codon Mutation: NMR Shielding Study
2008
P53 is one of the gene that has important role in human cell cycle and in the human cancers too. Models of codon substitution make it possible to separate mutational biases in the DNA from selective constraints on the protein, and offer a great advantage over amino acid models for understanding the evolutionary process of proteins and protein-coding DNA sequences. In this work, we investigated about CUA codon in exon5 of p53 that has mutated to CCA codon. We studied solvent effects on CUA codon by theoretical method, because the most of biological systems studied in solution and solvents have essential role in mutation of genes. Five solvents consist of acetone, ethanol, methanol, DMSO and water are predicated using ab initio method. Also, indirect (Au ind) solvent effects are obtained and NMR shielding tensors (ppm) have been computed with the continuous set of the gauge independent atomic orbital (GIAO) method.
European Journal of Biochemistry, 2005
2',3'-5'-Tri-O-acetyl[l,3,7,9,umin0-'~N]adenosine (ac3Ado) and its 8- 'H and 8-bromo derivatives (ac3[8-2H]Ado and ac3br'Ado) were synthesized from 95 "N-enriched adenosine which was obtained by microbial fermentation. The chemical shifts and nuclear Overhauser effects of 15N NMR of the adenosine derivatives were measurcd by changing the concentration of the mixed 1 -cyclohexyluracil (cHxUra) in chloroform. The limiting shift of each 15N resonance was calculated by using the association constants obtained from proton magnetic resonances of the ac3Ado/cHxUra and ac3br8Ado/cHxUra systems. From the quantitative analysis of the "N chemical shifts of the N-I and N-7 atoms it could be concluded that ac3Ado . cHxUra dimers prefer the Hoogsteen-type pair while the Watson-Crick-type pairs are predominant in the ac3br'Ado . cHxUra dimers. The N-3 atom, which does not locate at the interaction site, showed a fairly large induced shift. Thus the induced shift of "N resonance by association does not always mean the involvement of the corresponding nucleus to the interaction site. The effect of intermolecular hydrogen bonding on the nuclear Overhauser enhancement of the ' "-7 resonance was observed in the ac3[8-'H]Ado/cHxUra mixture. The presence of the Hoogsteen-type hydrogen bonding was proposed by the use of "N NMR spectra. The present information will be useful for the elucidation of non-Watson-Crick-type base-pair interaction in transfer RNA and oligonucleotides.
Biochemistry, 1986
In order to evaluate models for the acid denaturation of D N A and to assess the potential importance of protonated bases in mutations and gene expression, an N M R investigation of D N A and nucleotides in the pH range 7-2 has been conducted. The changes in the imino proton spectral region are readily observed and quite dramatic on lowering pH. At pH 7.0, calf thymus D N A has imino proton signals for A T (13.6 ppm, 56% area) and GC (12.6 ppm, 44% area) base pairs but no peaks in the 10-12 ppm region. At pH 5 a broad peak(s) between 10 and 11 ppm was (were) observed, and it narrowed and shifted to 10.
International journal of nanomedicine, 2011
The p53 tumor-suppressor protein is a cellular phosphoprotein and a negative regulator of cell growth. Most p53 mutations occur in exons 5-8 within the DNA-binding domain. Therefore, p53 can potentially be targeted with novel drugs designed to bind to a mutation and restore its stability or wild-type conformation. For the current study, Hartree-Fock calculations were used to investigate the solvent-induced effects of five different solvent media (acetone, ethanol, methanol, dimethyl sulfoxide, and water) on the thermochemical parameters and relative energies, and on the multinuclear nuclear magnetic resonance shielding tensors of oxygen, nitrogen, and phosphorus nuclei, of GAT. To understand how the solvent affects the mutation region (the "hot spot") of p53, the relative energies of GAT in selected solvent media were determined. Some biological evidence suggested the structural stabilities of hot spots of GAT have the optimum temperature and solvent type for mutation. All...
This work deals with tautomeric transformations of uracil (Ura) and thymine (Thy) in their model complexes with the deprotonated carboxylic group. Essential changes in the UV spectra of the bases upon their interaction with NaAc, vanishing signals of both imino protons in (1)H NMR spectra, and a perceptible decrease in intensity of both IR bands, related to the stretching vibrations nu(C=O) of the carbonyl groups, imply involvement of enolic tautomers. Results of quantum chemical calculations of the double complexes of the Ura(Thy) tautomers with CH(3)COO(-) at the MP2/6-311++G(2df,pd)//B3LYP/6-311++G(d,p) level of theory proved to be incompatible with the spectral features: despite the fact that the complexes of the enolic tautomers are much closer in energy to the diketo ones as compared to isolated tautomers, the energy gap between them is such that in tautomeric equilibrium dominate diketo forms. Calculations of triple complexes of the type CH(3)COO(-):Ura(Thy) tautomer:Na(+), taking into account the effect of the Na(+) coordination with tautomers, show that three triple complexes formed by enolic tautomers appeared more stable than those formed by diketo ones. This makes the UV and (1)H NMR data understandable, but the high residual intensity of the nu(C=O) bands in the IR spectra remains unclear. At that ion, Na(+) itself was not able to disturb the tautomeric equilibrium in the coordination complexes of the type Ura(Thy) tautomer:Na(+). To evaluate the DMSO effect, the CPCM solvation model was applied to triple complexes of the Ura tautomers. It appeared that in the solution there is coexistence between the diketo and enolic tautomers in a ratio of 53%:47%. This makes possible reconciliation of our experimental data. The biological significance of high-energy tautomers of nucleotide bases is discussed.
The Journal of Physical Chemistry A, 2018
Density functional theory method in combination with a continuum solvation model are used 10 to understand the role of hydrogen bonding in interaction of tertiary nitrogen centers of 11 guanine and adenine with monoaqua and diaqua NAMI-A. In case of adenine, interaction of 12 N3 with monoaqua NAMI-A is preferred over N7 and N1 whereas N7 is preferred over N3 13 and N1 in diaqua ruthenium-adenine interaction. In monoaqua and diaqua NAMI-A-guanine 14 interaction N7 site is preferred over N3 site. Here, strength and number of H-bonds play 15 important role in stabilising intermediates and transition states involved in the interaction of 16 NAMI-A and purine bases. Atoms in molecules and Becke surface analysis confirms that 17 structural deformation in the geometry of base pairs of GC and AT dinucleotides occur upon 18 interaction of monoaqua and diaqua NAMI-A. We have also observed that disruption of base 19 pairs in diaqua adducts occurs more than monoaqua adducts. Which suggests that diaqua 20 NAMI-A could have better anticancer agent than monoaqua NAMI-A. This study can be 21 extended to envisage the potential applications of computational studies in the development 22 of new drugs and targeted drug delivery systems.
Journal of Chemical Theory and Computation, 2006
A method for the incorporation of thermal averaging into the calculation of nuclear magnetic resonance properties is given. These properties are computed using density functional theory, anharmonic first-order perturbation corrections to a normal-mode analysis, and standard statistical mechanical averaging. The method is applied to the calculation of chemical shieldings and spin-spin coupling constants (J couplings) of 1′-imidazolyl-2′-deoxy-ribofuranose (IDR), a model compound for purine nucleosides, at the B3LYP/6-311++G(2d,p) level of theory. Thermal averaging causes substantial changes in the values of computed parameters. The calculated harmonic normal modes of IDR are also investigated; we find reasonable agreement with published results from vibrational spectroscopy on DNA fragments. Finally, the calculated magnetic and structural data regarding the reported hydrogen bond between H8 on the imidazole ring and O5′ on the sugar ring are investigated; we find that such data do not strongly support the formation of a hydrogen bond between these two atoms.
Hydrogen Bonding Effects on the 15N and 1H Shielding Tensors in Nucleic Acid Base Pairs
Journal of Magnetic Resonance, 2000
The results of systematic ab initio calculations of 15 N and 1 H chemical shielding tensors in the GC base pair as a function of hydrogen bond length are presented for the first time. The hydrogen bond length characterized by the distance r N. . .N between purine N1 and pyrimidine N3 was varied between 2.57 and 3.50 Å and the chemical shift tensors were calculated by the sum-overstates density functional perturbation theory. It is shown that the hydrogen bond length has a strong effect on the chemical shielding tensor of both imino proton and nitrogen, on their orientation, and, as a consequence, on the relaxation properties of both nuclei. For a nitrogen nucleus not involved in hydrogen bonding, the shielding tensor is nearly axially symmetric and almost collinear with the bond vector. As the length of the hydrogen bond decreases, the least shielding component 11 deflects from the N-H vector and the shielding tensor becomes increasingly asymmetric. The significance of the presented results for the analysis of relaxation data and the efficiency of TROSY effects together with a summary of the relevant shielding parameters are presented and discussed.