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Carcinogenesis, Vol. 21, No. 9, 1727-1736, September 2000
© 2000 Oxford University Press

Carcinogenesis

Sequence-dependent conformational perturbation in DNA duplexes containing an {epsilon}A•T mismatch using molecular dynamics simulation

Anton B. Guliaev, János Sági1 and B. Singer2

Donner Laboratory, Life Sciences Division, Lawrence Berkeley National Laboratory University of California, Berkeley, CA 94720, USA and
1 Institute of Chemistry, Chemical Research Center, Hungarian Academy of Sciences, H-1525 Budapest, PO Box17, Hungary

Previous experiments from this laboratory showed that 1,N6-ethenoadenine ({epsilon}A) in 15mer DNA oligonucleotide duplexes with GG{epsilon}AGG and CC{epsilon}ACC central sequences is repaired 3–5-fold more efficiently than in duplexes containing AA{epsilon}AAA and TT{epsilon}ATT central sequences. This sequence dependence in repair rates appeared to correlate with the observed thermodynamic stability of these duplexes [Hang et al. (1998) J. Biol. Chem., 273, 33406–33413]. In the present work, unrestrained molecular dynamics was used to evaluate the sequence-dependent structural features of these duplexes. Explicit solvent and the particle mesh Ewald method were applied for the accurate representation of the electrostatic interactions. The differences observed in the axis- and intra-base pair parameters were primarily localized at the {epsilon}A•T mismatch in all sequences and indicate conformational diversity between the structures. However, all four structures remained in the B-conformational family. In the tip, tilt and propeller twist parameters for the five central base pairs, larger perturbations were found for the two duplexes with {epsilon}A flanked by A or T bases than for duplexes with {epsilon}A flanked by G or C bases. As a result of these perturbations, the average global curvature of the AA{epsilon}AAA and TT{varepsilon}ATT DNA duplexes was larger by ~12° than that of the duplexes with the GG{epsilon}AGG and CC{epsilon}ACC central sequences. The observed conformational differences between the duplexes containing A or T and G or C neighbors of {epsilon}A may contribute to the observed differential enzymatic repair of the same sequences.


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