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

Abstract

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.