RNA is increasing appreciated for its numerous roles in biology. The Mathews lab uses computation to model RNA, from identification of novel RNA genes, to structure prediction, and to modeling conformational changes. This talk will focus on all-atom modeling with the AMBER force field. Recent advances have dramatically improved the force field, and we have been testing the limitations of the latest AMBER force field.
First, the ability of the Amber ff99 force field to predict relative free energies of RNA helix formation was investigated. The test systems were three hexaloop RNA hairpins with identical loops and varying stems. The free energy change of stretching the hairpins from the native state to an extended conformation was calculated with umbrella sampling. Using thermodynamic cycles, we demonstrated that the ff99 force field is able to accurately model relative free energies of RNA helix formation.
In a separate study, we modeled the conformational preference of tandem Guanine-Adenine (GA) non-canonical pairs in RNA. Previous solution structures showed that these tandem GA pairs adopt either imino or sheared conformations depending on the sequence and orientation of the adjacent closing base pairs. For the structures to maintain their native conformations during molecular dynamics simulations, a modification to the standard Amber ff10 force field was required, which allowed the amino group of guanine to leave the plane of the base and form out-of-plane hydrogen bonds with a cross-strand cytosine or uracil. Free energy change calculations for each sequence demonstrated the correct conformational preference when the force field modification was used, but the extent of the preference is underestimated.
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