Conformational Flexibility of C8-Phenoxyl-2′-deoxyguanosine Nucleotide Adducts

Abstract

Previous computational work suggests that isolated C8-phenoxyl-2'-deoxyguanosine nucleoside adducts preferentially adopt a syn orientation about the glycosidic bond, which is the first step in the mechanism by which many bulky C8 adducts exert their mutagenic effects. Since it is not clear whether these results can be directly extrapolated to the preferred conformation in DNA helices, approaches that more accurately reflect the physiological environment were used in the present study to understand the anti/syn preference of the ortho and para C8-phenoxyl-2'-deoxyguanosine adducts. Using nucleoside models and methods (B3LYP) similar to those previously implemented, we determine that the syn conformer is less stable than previously predicted when geometries relevant to B-DNA are considered. This indicates that the conformational energy trend is model dependent and stresses the importance of considering models that better mimic the DNA environment when determining the conformational preference of damaged bases. Therefore, we expanded our computational model to include the 5'-monophosphate group. Since the correct anti/syn energy trend for 2'-deoxyguanosine (dG) 5'-monophosphate has only been found using very specific computational models and prior knowledge of the biologically relevant nucleotide conformation, which is unavailable for most damaged systems, we initially benchmark our computational approach by studying the natural nucleotide. Despite the wide use of gas-phase optimizations in the current literature, only through the implementation of solvation-phase optimizations, as well as the use of a counterion model for the phosphate backbone, is the correct anti/syn energy trend predicted. Indeed, this is the first time in the literature that a biologically relevant syn structure is characterized for dG using methods suitable for studying bulky DNA adducts. Subsequently, our newly identified approach for DNA lesions was used to study C8-phenoxyl DNA adducts. In contrast to previously published results, we predict that the ortho and para adducts may adopt both the anti and syn conformations in DNA helices. These results have implications for the base-pairing properties and mutagenicity of these adducts, which must be further considered in future work.

Adenine versus guanine DNA adducts of aristolochic acids: role of the carcinogen–purine linkage in the differential global genomic repair propensity

“…In this model, the phosphate oxygen bonded to the 5′-neighboring nucleotide in DNA was capped with a hydrogen atom and the Na + ion was placed between the two non-capped phosphate oxygens. The structures were energy minimized in water using PCM-B3LYP-D3/6–31G(d), since our previous study has shown that the structural properties of modified nucleotides are best characterized in solvent (water) with a sodium ion to counter the phosphate charge ( 55 ). Single-point energy calculations were carried out using B3LYP-D3/6–311+G(2df,p) for the nucleobase and nucleoside minima and PCM-B3LYP-D3/6–311+G(2df,p) for the nucleotide minima.…”

C-Linked 8-aryl guanine nucleobase adducts: biological outcomes and utility as fluorescent probes

“… 64 Calculations (B3LYP/6-31G(d)) reveal that anti -structures are less stable than syn -structures, mainly since all syn minima contain an O5′–H···N3 hydrogen bond (1.80–1.96 Å). 55 , 65 – 67 The predicted syn -preference for the C-linked 8arylG nucleosides is supported by NMR spectra that exhibit a downfield shift of H2′, C1′, C3′ and C4′ and an upfield shift of C2′ compared to the corresponding signals for native G. 67 , 68 Solid-state structures of C-linked 8arylG nucleosides, including an 8-quinolyl derivative (QG) 24 and an ( N , N -dimethylaniline)guanosine analog, 69 are also syn . As a specific example, DFT calculations predict the syn orientation of the smallest (unsubstituted) 8-phenylG (PhG) derivative ( Fig.…”

Characterization of photophysical and base-mimicking properties of a novel fluorescent adenine analogue in DNA

“…It has also been shown previously that many 8-substituted purines show a preference for the syn conformation (55,56). However, calculations suggested a syn / anti equilibrium to be present in DNA helices for other analogues (57). The preferred orientation of the modified base around the glycosidic bond in duplex DNA depends on the hydrogen bonding preferences, which can change depending on the bulky substituent and can improve the relative stability of Hoogsteen pairs.…”