A theoretical study of the effect of methylation or ethylation at O6-guanine in the structure and energy of DNA double strands

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Abstract
Quantum and molecular mechanical calculations were employed to examine the effect on binding energies and structure of methylation and ethylation at O 6 -guanine in double-stranded DNA. Ab initio quantum chemical calculations (STO-3G, 3–21G) were initially used to pseudo-optimize the structure of the 9-methyl derivative of O 6 -methylguanine. The distal orientation for the O 6 -methyl group was found to be lower in energy than the proximal orientation. The geometry determined for the distal O 6 -methyl group was in agreement with recent X-ray work. These results were used in supplementary parameterization of the AMBER molecular mechanics force field necessary for the minimization of DNA double strands containing O 6 -methylguanosine. Resulting calculations with AMBER on two 5-mer DNA sequences containing the promutagenic G(GM)A subsequence showed that the proximal orientation, while higher in energy in the isolated molecule, is both less disruptive to the DNA double helix and more stable than the distal orientation. Binding energies and degree of destabilization upon methylation were found to be functions of the adjacent bases around a GGA subsequence. Sequence-dependent destabilization could play a role in the repair of alkylated bases. Quantum and molecular mechanics calculations indicate that the O 6 -methyl and O 6 -ethylguanines behave energetically in a very similar manner. These calculations suggest that the necessity for the different repair mechanisms for methylation and ethylation lesions cannot be simply explained by energy differences or observed structural differences.

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