Sequence-dependent conformational perturbation in DNA duplexes containing an epsilon A center dot T mismatch using molecular dynamics simulation

Previous experiments from this laboratory showed that 1,N-6-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 i n duplexes containing AA epsilon AAA and TT epsilon ATT central sequences. This sequence dependence in repair rates appeared to correlate with the obs erved thermodynamic stability of these duplexes [Hang et al, (1998) J, Biol , Chem,, 273, 33406-33413], In the present work, unrestrained molecular dyn amics was used to evaluate the sequence-dependent structural features of th ese duplexes. Explicit solvent and the particle mesh Ewald method were appl ied for the accurate representation of the electrostatic interactions. The differences observed in the axis- and intra-base pair parameters were prima rily localized at the epsilon A.T mismatch in all sequences and indicate co nformational diversity between the structures. However, all four structures remained in the B-conformational family, In the tip, tilt and propeller tw ist parameters for the five central base pairs, larger perturbations were f ound for the two duplexes with epsilon A flanked by A or T bases than for d uplexes with epsilon A flanked by G or C bases. As a result of these pertur bations, the average global curvature of the AA epsilon AAA and TT epsilon ATT DNA duplexes was larger by similar to 12 degrees than that of the duple xes with the GG epsilon AGG and CC epsilon ACC central sequences. The obser ved conformational differences between the duplexes containing A or T and G or C neighbors of epsilon A may contribute to the observed differential en zymatic repair of the same sequences.