Abstract
We apply continuum solvent models to investigate the relative stability of various conformational forms for two RNA sequences, GGAC(UUCG)GUCC and GGUG(UGAA)CACC. In the first part, we compare alternate hairpin conformations to explore the reliability of these models to discriminate between different local conformations. A second part looks at the hairpin-duplex conversion for the UUCG sequence, identifying major contributors to the thermodynamics of a much large scale transition. 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; non-electrostatic 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 and with earlier solvated molecular dynamics simulations, the UUCG hairpin was found to prefer conformera close to a recent NMR structure determination in preference to those from an earlier NMR study. Similarly, results for the UGAA hairpin favored an NMR-derived structure over that to be expected for a generic GNRA hairpin loop. Experimental free energies are not known for the hairpin/duplex conversion, but must be close to zero since hairpins are seen in solution and duplexes in crystals; out calculations find a value near zero and illustrate the expected interplay of solvation, salt effects and entropy in affecting this equilibrium.