A structure-based investigation on the binding interaction of hydroxylated polycyclic aromatic hydrocarbons with DNA

Binding of polycyclic aromatic hydrocarbons (PAHs) with DNA is one of the key steps in their mutagenic process. In this work, a previously established electrochemical displacement method was utilized to measure the binding constants (K-b) of 26 hydroxylated PAHs (OH-PAHs) with DNA. Eighteen OH-PAHs induced more than 50% signal reduction in the displacement measurement with calf thymus DNA, and K-b calculated from the EC50 value is between 8.3 x 10(4) and 3.0 x 10(5) M-1. Other eight OH-PAHs induced less than 50% signal reduction. For the latter compounds, EC50 values were obtained by fitting the displacement curve with a bi-exponential decay function and extrapolating it to 50% signal. K-b was then calculated, and was found to be in the range of 4.5 x 10(4) and 7.6 x 10(4) M-1. Measurements with polydG.polydC (pdGC) and polydA.polydT (pdAT) demonstrate that the OH-PAHs have no obvious selectivity toward DNA base pairs. In atomic force microscopy, a clear morphological change of calf thymus DNA from linear type to condensation form was observed after binding with 9-hydroxyfluorene. The change is similar to the one observed with the DNA-intercalating electrochemical indicator, suggesting that 9-hydroxyfluorene binds with DNA also by intercalation. An examination of the relationship between the molecular structure characteristics of the 26 OH-PAHs and their DNA-binding affinity revealed that the most positive net atomic charge on a hydrogen atom (q(H)(+)) correlated significantly with K-b at 0.05 level, with sig. (2-tailed) of 0.015. The correlation suggests that hydrogen bonding may play an important role in DNA/OH-PAH binding interaction. It was further revealed that Connolly accessible area (CAA), Connolly molecular area (CMA), and Connolly solvent-excluded volume (CSEV) of the nine hydroxybenzo[a]pyrenes correlated significantly with K-b at 0.01 or 0.05 level, with sig. (2-tailed) 0.019, 0.012 and 0.009, implying that steric effect might be an important factor in the binding of differently substituted OH-PAH with DNA. (C) 2009 Elsevier Ireland Ltd. All rights reserved.