CONTINUUM SOLVENT STUDIES OF THE STABILITY OF DNA, RNA, AND PHOSPHORAMIDATE - DNA HELICES

We apply continuum solvent models to investigate the relative stabilit y of A- and B-form helices for three DNA sequences, d(CCAACGTTGG)(2), d(ACCCGCGGGT)(2), and d(CGCGAATTCGCG)(2), a phosphoramidate-modified D NA duplex, p(CGCGAATTCGCG)(2), in which the O3' atom in deoxyribose is replaced with NH, and an RNA duplex, r(CCAACGUUGG)(2). Structures wer e taken as snapshots from multi-nanosecond molecular dynamics simulati ons computed in a consistent fashion using explicit solvent and with l ong-range electrostatics accounted for using the particle-mesh Ewald p rocedure. The electrostatic contribution to solvation energies were co mputed using both a finite-difference Poisson-Boltzmann (PB) model and a pairwise generalized Born model; nonelectrostatic contributions wer e estimated with a surface-area-dependent term. To these solvation fre e energies were added the mean solute internal energies (determined fr om a molecular mechanics potential) and estimates of the solute entrop y (from a harmonic analysis). Consistent with experiment, the relative energies favor B-form helices for DNA and A-form helices for the NP-m odified system and for RNA. Salt effects, modeled at the linear or non linear PB level, favor the A-form helices by modest amounts; for d(ACC CGCGGGT)(2), salt is nearly able to switch the conformational preferen ce to ''A''. The results provide a physical interpretation for the ori gins of the relative stabilities of A- and B-helices and suggest that similar analyses might be useful in a variety of nucleic acid conforma tional problems.