The chemical nature of the 2′-substituent in the pentose-sugar dictates the pseudoaromatic character of the nucleobase (pKa) in DNA/RNA
| Autor: | Dmytro Honcharenko, Subhrangsu Chatterjee, Jyoti Chattopadhyaya, Oleksandr Plashkevych, Mohitosh Maiti, Wimal Pathmasiri, Oommen P. Varghese |
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| Rok vydání: | 2006 |
| Předmět: |
Models
Molecular Magnetic Resonance Spectroscopy Pyrimidine Stereochemistry Chemical shift Pentoses Organic Chemistry Titrimetry Ab initio Nucleosides Protonation DNA Hydrogen-Ion Concentration Hydrocarbons Aromatic Biochemistry Organophosphates Acid dissociation constant Nucleobase chemistry.chemical_compound chemistry RNA Chemical stability Physical and Theoretical Chemistry Nucleoside |
| Zdroj: | Org. Biomol. Chem.. 4:1675-1686 |
| ISSN: | 1477-0539 1477-0520 |
| DOI: | 10.1039/b601460g |
| Popis: | We here show that the pKa (error limit: 0.01 to 0.03 pKa unit) of a nucleobase in a nucleotide can be modulated by the chemical nature of the 2'-substituent at the sugar moiety. This has been evidenced by the measurement of nucleobase pKa in 47 different model nucleoside 3',5'-bis- and 3'-mono-ethylphosphates. The fact that the electronic character of each of the 2'-substituents (Fig. 1) alters the chemical shift of the H2' sugar proton, and also alters the pKa of the nucleobase in the nucleotides has been evidenced by a correlation plot of pKa of N3 of pyrimidine (T/C/U) or pKa of N7 of 9-guaninyl with the corresponding deltaH2' chemical shifts at the neutral pH, which shows linear correlation with high Pearson's correlation coefficients (R = 0.85-0.97). That this modulation of the pKa of the nucleobase by a 2'-substituent is a through-bond as well as through-space effect has been proven by ab initio determined pKa estimation. Interestingly, experimental pKas of nucleobases from NMR titration and the calculated pKas (by ab initio calculations utilizing closed shell HF 6-31G** basis set) are linearly correlated with R = 0.98. It has also been observed that the difference of ground and protonated/de-protonated HOMO orbital energies (DeltaHOMO, a.u.) for the nucleobases (A/G/C/T/U) are well correlated with their pK(a)s in different 2'-substituted 3',5'-bis-ethylphosphate analogs suggesting that only the orbital energy of HOMO can be successfully used to predict the modulation of the chemical reactivity of the nucleobase by the 2'-substituent. It has also been demonstrated that pKa values of nucleobases in 3',5'-bis-ethylphosphates (Table 1) are well correlated with the change in dipole moment for the respective nucleobases after protonation or de-protonation. This work thus unambiguously shows that alteration of the thermodynamic stability (Tm) of the donor-acceptor complexes [ref. 20], as found with various 2'-modified duplexes in the antisense, siRNA or in triplexes by many workers in the field, is a result of alteration of the pseudoaromatic character of the nucleobases engineered by alteration of the chemical nature of the 2'-substitution. |
| Databáze: | OpenAIRE |
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