Research paper Activation barriers for methylation of DNA bases by dimethyl sulfate Daniel R. Eichler, George A. Papadantonakis ⇑ Department of Chemistry, University of Illinois at Chicago, 845 W. Taylor St., Room 4500 SES, Chicago, IL 60607, United States article info Article history: Received 31 July 2017 In final form 2 October 2017 Available online 3 October 2017 abstract The S N 2 transition states of the methylation reaction of DNA bases with dimethyl sulfate were examined employing DFT/ M06-2X/6-31+G / and DFT/B3LYP-D3/6-311+G (2df, 2p) levels of theory. Solvation effects were examined using the conductor-like polarizable continuum model (CPCM). Calculation results and feedback from electrostatic potential maps show that in water, charge separation lowers the activation barriers relative to the gas phase for the reactions at N7 of guanine, N3 of adenine and cytosine. Also, the reaction at the O 6 site of guanine is governed by steric interference and exhibits a higher activation barrier in water. Ó 2017 Elsevier B.V. All rights reserved. 1. Introduction Dimethyl sulfate (DMS) can be found in the environment in its gas phase and in airborne particulate matter that primarily origi- nates from coal combustion [1]. The proposed use of methanol as an alternative fuel could increase exposure to significant levels of DMS with consequences affecting quality of life [2]. Hydrolysis of DMS and the subsequent methylation of DNA in cells is responsible for systemic toxic effects principally on the nervous system, heart, liver, kidneys and possible carcinogenicity [3]. DMS is a monofunctional strong alkylating agent and reacts rapidly with DNA at room temperature and penetrates intact cells [4,5]. DMS methylates predominately nitrogen sites, such as the N7 of guanine at the major groove and N3 of adenine at the minor groove in double-stranded DNA. In single-stranded DNA, DMS methylates the N7 site of guanine; the N1, N3 and N7 sites of ade- nine; and the N3 site of cytosine [4,6]. DMS both in vivo and in vitro can be used to identify the guanines that interact with protein in the major groove and adenines that interact with protein in the minor groove [7]. DMS can methylate the O 6 site of guanine and cause direct mispairing. This is relevant because the O 6 site of gua- nine is significant in mutagenesis [8]. Also, cases of lung cancer, bronchial carcinoma and choriodal melanoma were reported in men exposed occupationally to DMS [9,10]. Lastly, the EPA has classified DMS as a Group B2, probable human carcinogen [11]. In addition, the impact of the O 6 -methylation of guanosine on the relaxation mechanism of guanine monomers was reported in an experimental femtosecond laser study where the absorption spectrum is red-shifted and this resulted in a 40-fold decrease of the excited-state decay which increases the probability of radiation induced damage of cellular DNA [12]. In light of these reports, further investigation of the methylation of DNA bases by DMS becomes imperative. The methylation of DNA bases by DMS occurs through a bimolecular S N 2 nucleophilic substitution mechanism [13,14] and the experimental selectivity [4] observed in different sites is a strong indication that activation barriers exist. In theoretical investigations of DNA alkylation reac- tions, many studies have focused on the reactivity of methane dia- zonium ion with guanine [15,16]. These studies have shown that activation barriers are influenced by local ionization energy and steric interference. It was also reported that activation energies are significantly higher at the O 6 than at the N7 sites and are slightly higher in solution than in the gas phase [16]. In a study investigating the steric retardation of S N 2 reactions in the gas phase and solution considering the reaction of chloride with ethyl and neopentyl chlorides and their a-cyano derivatives employing B3LYP, CBS-QB3 and PDDG/PM3 levels of theory for the gas phase and QM/MM Monte Carlo simulations for different solvents such as DMSO, methanol and water, as well as with the polarizable continuum model, CPCM, it was reported that steric effects raise the activation energy by 6 kcal/mol for the tert-butyl group relative to methyl for both cases and solvents cause a large increase in the activation energies for these reactions [17]. In an investigation of the S N 2 reaction between chloride and chloramine in dimethyl ether solution employing quantum mechanical calcu- lations at the 6-311+G // /MP2 and 6-311+G (2d, p)/MP2 level for the gas phase and classical force field to describe the solvent, it was described that the solvent made the ion-dipole complex well more shallow by 6.4 kcal/mol and raised the barrier for the reac- tion in solution to 15.0 kcal/mol [18]. In another study employing the VENUS chemical dynamics program interfaced with the NWChem electronic structure program, it was conveyed that the https://doi.org/10.1016/j.cplett.2017.10.003 0009-2614/Ó 2017 Elsevier B.V. All rights reserved. ⇑ Corresponding author. E-mail address: gpapad3@uic.edu (G.A. Papadantonakis). Chemical Physics Letters 689 (2017) 8–14 Contents lists available at ScienceDirect Chemical Physics Letters journal homepage: www.elsevier.com/locate/cplett