Modeling the Conformational Preference of the Carbon-Bonded Covalent Adduct Formed upon Exposure of 2′-Deoxyguanosine to Ochratoxin A

Abstract

The conformational flexibility of the C8-linked guanine adduct formed from attachment of ochratoxin A (OTA) was analyzed using a systematic computational approach and models ranging from the nucleobase to the adducted DNA helix. A focus was placed on the influence of the C8-modification of 2'-deoxyguanosine (dG) on the preferred relative arrangement of the nucleobase and the C8-substituent and, more importantly, the anti/syn conformational preference with respect to the glycosidic bond. Although OTA is twisted with respect to the base in the nucleobase model, addition of the deoxyribose sugar induces a further twist and restricts rotation about the C-C linkage due to close contacts between OTA and the sugar. The nucleoside model preferentially adpots a syn orientation (by 10-20 kJ mol(-1) depending on the OTA conformation) due to the presence of an O5'-H···N3 interaction. However, when this hydrogen bond is eliminated, which better mimics the DNA environment, a small (<5 kJ mol(-1)) anti/syn energy difference is predicted. Inclusion of the 5'-monophosphate group leads to an up to 20 kJ mol(-1) preference for the syn (nucleotide) conformation due to stabilizing base-phosphate interactions involving the amino group of guanine. Nevertheless, MD simulations and free energy analysis predict that both syn- and anti-conformations of OTB-dG are equally stable in helices when paired opposite cytosine. These results indicate that the adduct will likely adopt a syn conformation in an isolated nucleoside and nucleotide, while a mixture of syn and anti conformations will be observed in DNA duplexes. Since the syn conformation could stabilize base mismatches upon DNA replication or Z-DNA structures with varied biological outcomes, future computational and experimental work should elucidate the consequences of the conformational preference of this potentially harmful DNA lesion.

Effect of base sequence context on the conformational heterogeneity of aristolactam-I adducted DNA: structural and energetic insights into sequence-dependent repair and mutagenicity

“…Although the currently available (computational) structural details of ALI-N 6 -dA adducted DNA have only been obtained in a single (CXC) sequence context, 29 previous studies on a variety of carcinogenic adducts, including those formed from aromatic amines, [36][37][38][39] PAHs, 35,[40][41][42][43] and ochratoxin A, 44,45 point towards the sequence dependence of the conformational preference of damaged DNA. Specifically, changes in the sequence at the lesion site can affect key structural features and alter the stability of the preferred conformational theme of adducted DNA.…”

Non-Canonical Helical Structure of Nucleic Acids Containing Base-Modified Nucleotides

“…The acetylaminofluorene (AAF) and aminofluorene (AF) adducts substituted into the C8 position of guanosine incorporated in poly(dG-dC)-AAF can adopt Z-form DNA without the presence of alcohol [98]. Recently, it was reported that guanosine inserted by ochratoxin A (OTA) into the C8 position can also adapt Z-form conformations, such as AAF and AF [99][100][101]. The 8-aryl-dG also destabilizes the B-DNA conformation and favors the Z-DNA conformation, since the steric factor helps glycosidic bond rotation to form syn conformations [32].…”

Assessment of the electronic structure and properties of trichothecene toxins using density functional theory

“…Type B trichothecenes possess a carbonyl in the R5 position and include compounds 1-10, and 29. This study also includes the type A trichothecene T-2 toxin and related compounds (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). T-2 toxin is associated with a variety of harmful effects, including alimentary toxic aleukia, and is a possible war agent [1].…”

“…These calculations describe the quantum nature of materials using an exchange-correlation functional, and have been highly successful in providing insight into structure based phenomena that are difficult to study experimentally [8,9]. Density functional studies have provided important information on toxin structures [10][11][12][13][14][15]; however, these methods have only been applied to a few trichothecene toxins. DFT studies at the B3LYP/6-31G(d,p) level of theory on the tautomers of deoxynivalenol and nivalenol gave additional structural insight into tautomer preferences and the interpretation of experimental IR and physical data [16,17].…”