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Activation barriers for DNA alkylation by carcinogenic methane diazonium ions
Author(s) -
Ekanayake Kaushalya S.,
Lebreton Pierre R.
Publication year - 2006
Publication title -
journal of computational chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.907
H-Index - 188
eISSN - 1096-987X
pISSN - 0192-8651
DOI - 10.1002/jcc.20334
Subject(s) - chemistry , solvation , guanine , transition state , reactivity (psychology) , density functional theory , molecule , thymine , computational chemistry , photochemistry , dna , organic chemistry , medicine , nucleotide , biochemistry , alternative medicine , pathology , gene , catalysis
Methylation reactions of the DNA bases with the methane diazonium ion, which is the reactive intermediate formed from several carcinogenic methylating agents, were examined. The S N 2 transition states of the methylation reactions at N7, N3, and O 6 of guanine; N7, N3, and N1 of adenine; N3 and O 2 of cytosine; and O 2 and O 4 of thymine were calculated using the B3LYP density functional method. Solvation effects were examined using the conductor‐like polarizable continuum method and the combined discrete/SCRF method. The transition states for reactions at guanine N3, adenine N7, and adenine N1 are influenced by steric interactions between the methane diazonium ion and exocyclic amino groups. Both in the gas phase and in aqueous solution, the methylation reactions at N atoms have transition states that are looser, and generally occur earlier along the reaction pathways than reactions at O atoms. The forming bonds in the transition states in water are 0.03 to 0.13 Å shorter than those observed in the gas phase, and the activation energies are 13 to 35 kcal/mol higher. The combined discrete/SCRF solvation energy calculations using base‐water complexes with three water molecules yield base solvation energies that are larger than those obtained from the CPCM continuum method, especially for cytosine. Reactivities calculated using barriers obtained with the discrete/SCRF method are consistent with the experimentally observed high reactivity at N7 of guanine. © 2005 Wiley Periodicals, Inc. J Comput Chem 27: 277–286, 2006