Published: July 21, 2011 r2011 American Chemical Society 10537 dx.doi.org/10.1021/jp202738v | J. Phys. Chem. B 2011, 115, 10537–10546 ARTICLE pubs.acs.org/JPCB Model Calculations for the Misincorporation of Nucleotides Opposite Five-Membered Exocyclic DNA Adduct: N 2 ,3-Ethenoguanine Venkatesan Srinivasadesikan, Prabhat K. Sahu, and Shyi-Long Lee* Department of Chemistry and Biochemistry, National Chung Cheng University, Chia-Yi, 621 Taiwan b S Supporting Information ’ INTRODUCTION Five-membered exocyclic DNA adducts are biologically very significant because of their potential to block DNA replication and transcription, induce DNA strand breaks, trigger apoptosis, and cause gene mutations and chromosomal aberrations. These effects could lead directly to carcinogenesis. 1 Common exo- cyclic DNA adducts, such as 1,N 6 -ethenoadenine (εA), 3,N 4 - ethenocytosine (εC), N 2 ,3-ethenoguanine (N 2,3 - εG), and 1, N 2 -ethenoguanine (1,N 2 -εG), are responsible for blocking WatsonÀCrick base pairing. 2 The annelation products of exo- cyclic five-membered rings in DNA bases arising from the reactions of electrophiles from vinyl halides; vinyl monomers, including chloroacetaldehyde; and endogenous lipid peroxida- tion of malondialdehyde, crotonaldehyde, 4-hydroxy-2-nonenal, 4,5-epoxy-2(E)-decanal, 4-hydroperoxynonenal, and trans-fatty acids and their metabolic products are also of significance in the formation of DNA adducts. 3 Among the different five-membered DNA adducts, N 2 ,3-ethenoguanine (N 2,3 -εG) has been identi- fied in the liver DNA of vinyl chloride-exposed rats, the major route of human exposure. 4 Singer et al. 5 reported that misincor- poration of thymine (T), having two hydrogen bonds with N 2,3 -εG, represents the mutagenic event. Again, N 2,3 -εG is the only derivative formed in vivo by the human carcinogen vinyl chloride that can be shown to have a high probability of causing transitions that could initiate malignant transformation. 5 Cheng et al. 6 determined the base-pairing specificity of N 2,3 -εG in Escherichia coli through genetic reversion assay and concluded that N 2,3 -εG specifically induces G f A transitions, with 13% mutagenic potential. Failure of the mismatch repair system can lead to genomic instability, whereas damage in genes respon- sible for maintaining DNA stability can lead to the risk of developing cancer and many other debilitating diseases. 7 Un- derstanding the complexity of the recognition and repair of erroneous base pairing has been a major area of research in biological and medical communities for many decades. 8 Only limited computational studies of five-membered exocyclic DNA adducts for the determination of cancer etiology have been reported. 9 In this article, we report model calculations on the misincorporation of nucleotides opposite the five-membered exocyclic N 2 ,3-ethenoguanine adduct (N 2,3 -εG). The present study could provide useful information, such as geometric char- acteristics, electronic properties, and physical parameters, for the misincorporation of DNA nucleotides in the N 2 ,3-ethenoguanine adduct, based on different conformations and unique mutagenic properties that are essential for the continuous effort to under- stand the base-pairing specificity toward the determination of cancer etiology. Received: March 23, 2011 Revised: July 5, 2011 ABSTRACT: Five-membered exocyclic DNA adducts are biologically very significant because of their potential to block DNA replication and transcription. N 2 ,3-Ethenoguanine (N 2,3 -εG) has been identified in the liver DNA of vinyl chloride-exposed rats as a five-membered DNA adduct. Singer et al. (Carcinogenesis 1987, 8, 745À747) reported that the misincorporation of thymine (T), with two hydrogen bonds to N 2,3 -εG, represents the mutagenic event. Although the base- pairing specificity and mode of misincorporation have been studied experimentally for the N 2 ,3-ethenoguanine adduct, molecular-level information is not yet clear. In this study, we have considered all four different DNA nucleotides paired with the N 2 ,3-ethenoguanine adduct for model calculations toward the determination of base-pairing specificity. To provide insight into the mutagenic process of DNA damage based on geometric characteristics and electronic properties, the B3LYP and M06 methods were employed for these model calculations. Single-point energy calculations at the MP2/6-311++G** level on the corresponding optimized geometries were also carried out to better estimate the hydrogen-bonding strengths. The polarizable conductor calculation model (CPCM), which accounts for the overall polarizability of the solvent, was also employed. The computed reaction enthalpy values lie in the order εGÀG(2) (10.3 kcal/mol) > εGÀG(4) (9.6 kcal/mol) > εGÀT(4) (9.2 kcal/mol) > εGÀG(1) (9.1 kcal/mol) > εGÀA(5) (8.2 kcal/mol) > εGÀC(2) (7.9 kcal/mol) at the M06 level, which indicates that guanine and thymine are most favorable for mispairing with the N 2 ,3-ethenoguanine adduct.