title: 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.
authors.affiliation: Department of Chemistry and Biochemistry, University of Lethbridge , 4401 University Drive West, Lethbridge, Alberta T1K 3M4, Canada.
authors.forename: Purshotam
authors.initials: P
authors.lastname: Sharma
authors.forename: Richard A
authors.initials: RA
authors.lastname: Manderville
authors.forename: Stacey D
authors.initials: SD
authors.lastname: Wetmore
mesh_terms: D002244:Carbon / Q000737:chemistry*; D018736:DNA Adducts / Q000737:chemistry*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D009793:Ochratoxins / Q000737:chemistry*; D011789:Quantum Theory
chemical_list: D018736:DNA Adducts; D009793:Ochratoxins; C025589:ochratoxin A; D002244:Carbon; D003849:Deoxyguanosine