Continuum Solvent Studies of the Stability of DNA, RNA, and Phosphoramidate−DNA Helices

We apply continuum solvent models to investigate the relative stability of A- and B-form helices for three DNA sequences, d(CCAACGTTGG)2, d(ACCCGCGGGT)2, and d(CGCGAATTCGCG)2, a phosphoramidate-modified DNA duplex, p(CGCGAATTCGCG)2, in which the O3‘ atom in deoxyribose is replaced with NH, and an RNA duplex, r(CCAACGUUGG)2. Structures were taken as snapshots from multi-nanosecond molecular dynamics simulations computed in a consistent fashion using explicit solvent and with long-range electrostatics accounted for using the particle−mesh Ewald procedure. The electrostatic contribution to solvation energies were computed using both a finite-difference Poisson−Boltzmann (PB) model and a pairwise generalized Born model; nonelectrostatic contributions were estimated with a surface-area-dependent term. To these solvation free energies were added the mean solute internal energies (determined from a molecular mechanics potential) and estimates of the solute entropy (from a harmonic analysis). Consistent with experiment, the relative energies favor B-form helices for DNA and A-form helices for the NP-modified system and for RNA. Salt effects, modeled at the linear or nonlinear PB level, favor the A-form helices by modest amounts; for d(ACCCGCGGGT)2, salt is nearly able to switch the conformational preference to “A”. The results provide a physical interpretation for the origins of the relative stabilities of A- and B-helices and suggest that similar analyses might be useful in a variety of nucleic acid conformational problems.