Conformational Flexibility of C8-Phenoxylguanine Adducts in Deoxydinucleoside Monophosphates

M06-2X/6-31G(d,p) is used to calculate the structure of all natural deoxydinucleoside monophosphates with G in the 5′ or 3′ position, the <i>anti</i> or <i>syn</i> conformation, and each natural (A, C, G, T) base in the corresponding flanking position. When the <i>ortho</i> or <i>para</i> C8-phenoxyl-2′-deoxyguanosine (C8-phenoxyl-dG) adduct replaces G in each model, there is little change in the relative base–base orientation or backbone conformation. However, the orientation of the C8-phenoxyl group can be characterized according to the position (5′ versus 3′), conformation (<i>anti</i> versus <i>syn</i>), and isomer (<i>ortho</i> versus <i>para</i>) of damage. Although the degree of coplanarity between the phenoxyl ring and G base in the <i>ortho</i> adduct is highly affected by the sequence since the hydroxyl group can interact with neighboring bases, the <i>para</i> adduct generally does not exhibit discrete interactions with flanking bases. For both adducts, steric clashes between the phenoxyl group and the backbone or flanking base destabilize the <i>anti</i> conformation preferred by the natural nucleotide and thereby result in a clear preference for the <i>syn</i> conformation regardless of the sequence or position. This contrasts the conclusions drawn from smaller (nucleoside, nucleotide) models previously used in the literature, which stresses the importance of using models that address the steric constraints present due to the surrounding environment. Since replication errors for other C8-dG bulky adducts have been linked to a preference for the <i>syn</i> conformation, our findings provide insight into the possible mutagenicity of phenolic adducts.