Correlation between nmr spectral parameters of nucleosides and its implication to the conformation about the glycosyl bond

Cho, Bongsup P.; Evans, Frederick E.

doi:10.1016/s0006-291x(05)81288-4

Cited by 8 publications

(5 citation statements)

References 27 publications

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“…2008), even though in solution the syn conformation is expected to be dominant (Davies 1978; Stolarski et al. 1984; Cho and Evans 1991). This observation significantly simplifies the free energy calculations of the compounds in the binding site of the FtsZ protein, because the simulation can be restricted to a single ligand conformation and no high energy barriers need to be crossed.…”

Section: Introductionmentioning

confidence: 99%

Calculations of binding affinity between C8-substituted GTP analogs and the bacterial cell-division protein FtsZ

2010

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The FtsZ protein is a self-polymerizing GTPase that plays a central role in bacterial cell division. Several C8-substituted GTP analogs are known to inhibit the polymerization of FtsZ by competing for the same binding site as its endogenous activating ligand GTP. Free energy calculations of the relative binding affinities to FtsZ for a set of five C8-substituted GTP analogs were performed. The calculated values agree well with the available experimental data, and the main contribution to the free energy differences is determined to be the conformational restriction of the ligands. The dihedral angle distributions around the glycosidic bond of these compounds in water are known to vary considerably depending on the physicochemical properties of the substituent at C8. However, within the FtsZ protein, this substitution has a negligible influence on the dihedral angle distributions, which fall within the narrow range of −140° to −90° for all investigated compounds. The corresponding ensemble average of the coupling constants 3J(C4,H1′) is calculated to be 2.95 ± 0.1 Hz. The contribution of the conformational selection of the GTP analogs upon binding was quantified from the corresponding populations. The obtained restraining free energy values follow the same trend as the relative binding affinities to FtsZ, indicating their dominant contribution.

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Section: Introductionmentioning

confidence: 99%

Calculations of binding affinity between C8-substituted GTP analogs and the bacterial cell-division protein FtsZ

2010

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“…Analysis of the Karplus dependence of the J 1′,2′ (9.1-9.2 Hz) and J 3′,4′ (2.4-3.1 Hz) coupling constants observed for the three isomeric AP adducts (Table 1) indicated a strong preference for the C2′-endo (S) sugar puckering (49,62). A similar analysis of J 4′,5′ and J 4′,5" (48,50) showed a preference (81-85%) of gauche-gauche populations (gg) of the exocyclic C4′-C5′ bond. A slightly higher gg population (>90%) has been observed for the low-energy conformer of dG-C8-AF, whose N 8 H forms a hydrogen bond with O5′ (51).…”

Section: Resultsmentioning

confidence: 69%

“…Glycosyl Conformation. Among the NMR approaches for determining the dynamic anti − syn -glycosyl conformation of C8-substituted purine nucleosides or nucleotides, the chemical shift of the sugar H2‘ is regarded as a simple indicator ( , ). In general, deshielding of the H2‘ resonance relative to dG is considered as stemming from an increased population of syn conformers.…”

Section: Resultsmentioning

confidence: 99%

Synthesis, Characterization, and Comparative Conformational Analysis of N-(Deoxyguanosin-8-yl)aminopyrene Adducts Derived from the Isomeric Carcinogens 1-, 2-, and 4-Nitropyrene

Zhou

Cho

1998

Chem. Res. Toxicol.

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Nitrated polycyclic aromatic hydrocarbons are mutagens/carcinogens that undergo in vivo activation by ring-oxidation and nitro-reduction pathways. We report the syntheses and comparative conformational analyses of N-(deoxyguanosin-8-yl)-n-aminopyrene adducts (dG-C8-n-AP, n = 1, 2, 4) derived from the three isomeric mononitropyrenes (1-, 2-, and 4-NP). The C8-amine nitrogens of these adducts have been enriched with 15N to examine the conformation about the pyrenyl-nitrogen and guanyl-nitrogen bonds that link the guanine and the pyrene moiety. These adducts are structurally isomeric, thus providing an interesting opportunity for systematic probing of the isomeric adduct conformations. Spectroscopic data indicated that the three isomeric aminopyrene adducts favor anti-glycosyl conformations, with C2'-endo (S) sugar puckering and a nearly planar conformation at the central amine nitrogen. The data further indicated differences in the extent of pi-electron conjugations about the pyrenyl-nitrogen bond, depending on the location of aminopyrene substitution. Thus while the 1- and 4-isomers both have substitution adjacent to a fused aromatic ring, the 2-isomer is highly symmetric and less sterically hindered. The 2-isomer adopts the most planar conformation, thereby having the most efficient pi-electron delocalization between the guanine and pyrene rings. The isomeric dG-C8-AP adducts and their nitro and amino precursors display physicochemical properties (HPLC retention time, UV pattern, 1H NMR data, mass fragmentation, etc.) distinctly dependent on their structures (1- and 4-isomers versus 2-isomer).

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“…Energy minimized model structures (Figure 6) clearly indicated that they exist in the well-defined syn glycosidyl conformation, 40.8° (χ ∠O4’- C1’- N9-C8) and 61.6° (χ ∠O4’- C1’- N1-C6), respectively for cyclo-dG and cyclo-dT. This is contrasted with their noncyclic counterparts dG and dT, which are known to exist in flexible, but mostly anti conformation (χ =170-300°) 18. The rigidity of cyclo-dG and cyclo-dT allows the H1’ and H8 protons to be in a close spatial proximity, 2.5 and 2.2 Å, respectively (Figure 6).…”

Section: Resultsmentioning

confidence: 95%

“…Cyclo-dG (16) and cyclo-dT (17) are rigid cage-like molecules with well-defined syn-glycosidyl conformation, 40.8°(χ ∠O4′-C1′-N9-C8) and 61.6°(χ ∠O4′-C1′-N1-C6), respectively. 18 Such rigidity allows their H1′ and H8 protons to be in a close spatial proximity, 2.5 and 2.2 Å, respectively (Figure 6). This is evidenced by observations of strong NOEs in the NOESY spectrum of cyclo-dG (Figure 7).…”

Section: Resultsmentioning

confidence: 99%

α,β-Methylene-2′-deoxynucleoside 5′-Triphosphates as Noncleavable Substrates for DNA Polymerases: Isolation, Characterization, and Stability Studies of Novel 2′-Deoxycyclonucleosides, 3,5′-Cyclo-dG, and 2,5′-Cyclo-dT

et al. 2008

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The 2’-deoxynucleoside 5’-triphosphate (dNTP) analogs with modifications in the triphosphate chain have been used as nucleotide probes in various biochemical and structural studies. Here we report synthesis and characterization of a complete set of α,β-methylene-2’-dNTPs (α,β-m-dNTP; N = A, C, T, G, 12-15), in which the α,β-oxygen linkage of natural dNTP was replaced isosterically by a methylene group. These nucleotides were designed to be non-cleavable DNA polymerase substrates. Our synthesis process entails preparation of 2’-deoxynucleoside 5’-diphosphate precursors by nucleophilic coupling of 5’-tosyl nucleosides and methylene-diphosphate, and a subsequent enzymatic γ-phosphorylation. All four synthesized α,β-m-dNTPs were found to be potent inhibitors of polymerase β with Ki values ranging from 1-5 μM. During preparation of the dG and dT derivatives of α,β-methylene diphosphate, we isolated significant amounts of 3,5’-anhydro-2’-deoxyguanosine (cyclo-dG, 16) and 2,5’-anhydro-2’-deoxythymidine (cyclo-dT, 17), respectively. These novel 2’-deoxycyclonucleosides were formed via a base-catalyzed deprotonation of the imino proton (N1-H and N3-H), followed by an intramolecular cyclization (N3 → C5’ and O2 → C5’, respectively). In acidic solution, the cyclonucleosides underwent glycolysis at N9, followed by complete depurination at N3. In the case of cyclo-dG, there existed an equilibrium between glycolysis and deglycolysis at the glycosidic linkage prior to complete depurination. When exposed to alkaline conditions, cyclo-dG underwent an oxidative deamination at C2 to produce 3,5’-anhydro-2’-deoxyxanthosine (cyclo-dX, 19), whereas cyclo-dT was hydrolyzed exclusively to dT via cleavage at the 2,5’-ether linkage.

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Correlation between nmr spectral parameters of nucleosides and its implication to the conformation about the glycosyl bond

Cited by 8 publications

References 27 publications

Calculations of binding affinity between C8-substituted GTP analogs and the bacterial cell-division protein FtsZ

Calculations of binding affinity between C8-substituted GTP analogs and the bacterial cell-division protein FtsZ

Synthesis, Characterization, and Comparative Conformational Analysis of N-(Deoxyguanosin-8-yl)aminopyrene Adducts Derived from the Isomeric Carcinogens 1-, 2-, and 4-Nitropyrene

α,β-Methylene-2′-deoxynucleoside 5′-Triphosphates as Noncleavable Substrates for DNA Polymerases: Isolation, Characterization, and Stability Studies of Novel 2′-Deoxycyclonucleosides, 3,5′-Cyclo-dG, and 2,5′-Cyclo-dT

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