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

Abstract

Computational modeling is employed to provide a plausible structural explanation for the experimentally-observed differential global genome repair (GGR) propensity of the ALII-N(2)-dG and ALII-N(6)-dA DNA adducts of aristolochic acid II. Our modeling studies suggest that an intrinsic twist at the carcinogen-purine linkage of ALII-N(2)-dG induces lesion site structural perturbations and conformational heterogeneity of damaged DNA. These structural characteristics correlate with the relative repair propensities of AA-adducts, where GGR recognition occurs for ALII-N(2)-dG, but is evaded for intrinsically planar ALII-N(6)-dA that minimally distorts DNA and restricts the conformational flexibility of the damaged duplex. The present analysis on the ALII adduct model systems will inspire future experimental studies on these adducts, and thereby may extend the list of structural factors that directly correlate with the propensity for GGR recognition.

Figure 1.

Structure of (A) aristolochic acids, as well as the corresponding (B) AL-N⁶-dA and (C) AL-N²-dG adducts (R = OCH₃ for ALI and H for ALII). Definitions are provided for the θ (∠(N1C2N2C10)) and ϕ (∠(C2N2C10C11)) dihedral angles, which determine the orientation of the ALII moiety with respect to the base and χ (∠(O4′C1′N9C4)), which dictates the glycosidic bond orientation to be syn (90° > χ > −60°), high syn (120° > χ > 90°), anti (120° > χ > −90°) or high anti (−60° > χ > −90°). Dihedral angles β (∠(C4′C5′O5′H)) and ε (∠(C4′C3′O3′H)) govern the DNA sugar–phosphate backbone orientation.

Figure 2.

DFT (B3LYP-D3/6–31G(d)) minimum energy conformations of ALII-N⁶-dA (left) (46) and ALII-N²-dG (right) according to (A) nucleobase, (B) nucleoside, (C) 5′-OH constrained nucleoside and (D) nucleotide models.

Figure 3.

Base-pair trimers containing the lesion site in representative MD structures obtained from 20 ns simulations carried out independently on each energetically-accessible conformation of (A) ALII-N²-dG and (B) ALII-N⁶-dA adducted DNA. The relative free energies (kJ mol⁻¹) with respect to the lowest energy conformation for a given adduct are provided in parantheses.

Figure 4.

The pseudostep parameters and minor groove dimensions for different conformations of (A) ALII-N²-dG or (B) ALII-N⁶-dA (46) adducted DNA relative to the corresponding unmodified helix. The helical dynamics are indicated by error bars.

Figure 5.

Comparison of lesion van der Waals (stacking) energies for anti or syn ALII-N²-dG (solid lines) and ALII-N⁶-dA (dashed lines) in different adducted DNA conformations over 20 ns MD simulations.