Journal Article

Sequence-dependent conformational perturbation in DNA duplexes containing an ϵA•T mismatch using molecular dynamics simulation

Anton B. Guliaev, János Sági and B. Singer

in Carcinogenesis

Volume 21, issue 9, pages 1727-1736
Published in print September 2000 | ISSN: 0143-3334
Published online September 2000 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/21.9.1727
Sequence-dependent conformational perturbation in DNA duplexes containing an ϵA•T mismatch using molecular dynamics simulation

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Previous experiments from this laboratory showed that 1,N6-ethenoadenine (ϵA) in 15mer DNA oligonucleotide duplexes with GGϵAGG and CCϵACC central sequences is repaired 3–5-fold more efficiently than in duplexes containing AAϵAAA and TTϵATT 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 ϵA•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 ϵA flanked by A or T bases than for duplexes with ϵA flanked by G or C bases. As a result of these perturbations, the average global curvature of the AAϵAAA and TTεATT DNA duplexes was larger by ~12° than that of the duplexes with the GGϵAGG and CCϵACC central sequences. The observed conformational differences between the duplexes containing A or T and G or C neighbors of ϵA may contribute to the observed differential enzymatic repair of the same sequences.

Keywords: εA, 1,N6-ethenoadenine; MD, molecular dynamics; PME, particle mesh Ewald; r.m.s.d., root mean square deviation.

Journal Article.  6183 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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