Why do A.T base pairs inhibit Z-DNA formation?

Abstract

We have carried out free energy perturbation calculations on DNA double-stranded hexanucleotides. The sequence d(CGCGCG)2 has been "mutated" into d(CGTGCG).cntdot.d(CGCACG) with the oligonucleotide in the A, B, and Z structural forms, both in vacuo and in aqueous solution. In addition, model free energy calculations have been carried out in which the electrostatic charges of the H-bonding groups of the bases in the major and minor grooves of the DNA are reduced to zero as a way of assessing the relative solvation effects of these groups in the different structural forms of DNA. Finally, energy component analyses have been carried out to assess the relative roles of different intranucleotide interactions on the B .fwdarw. Z equilibrium as a function of base sequence. In vacuo, the free energy for changing a G.cntdot.C to an A.cntdot.T base pair is largest in the Z conformation; in the A and B conformations, the free energy cost is .apprxeq.2 kcal/mol lower (1 cal = 4.184J). The results are similar when the simulations are run in explicit solvent: the change costs 3 kcal/mol more in the Z conformation than in the B form. These results are consistent with experimental data, where it is clear that A.cntdot.T sequences are significantly more "Z-phobic" than G.cntdot.C sequences. The calculations indicate that both intranucleotide and solvation interactions contribute to this Z-phobicity.