39 Simulation of RNA tandem GA base pairs provides insights about the forces behind conformational preference

Abstract

Conformational changes are important for RNA function. We used molecular mechanics with all-atom models to understand conformational preference in RNA tandem guanine–adenine (GA) base pairs. These tandem GA base pairs play important roles in determining the stability and structural dynamics of RNA tertiary structures. Previous solution structures showed that these tandem GA base pairs adopt either imino (cis-Watson-Crick/cis-Watson-Crick interaction) or sheared (trans-Hoogsteen/trans-Hoogsteen interaction) pairing depending upon the sequence and orientation of the adjacent base pairs. In our simulations, we modeled (GCGGACGC)₂ (Wu and Turner 1996) and (GCGGAUGC)₂ (Tolbert et al., 2007), experimentally preferred as imino and sheared, respectively. Besides the experimentally preferred conformation, we constructed models of the nonnative conformations by changing cytosine to uracil or uracil to cytosine. We used explicit solvent molecular dynamics and free energy calculation with umbrella sampling to measure the free energy deference of the experimentally preferred conformation and the nonnative conformations. A modification to ff10 was required, which allowed the guanine bases’ amino group to leave the base plane (Yildirim et al., 2009). With this modification, the RMSD of unrestrained simulations and the free energy surfaces are improved, suggesting the importance of electrostatic interactions by G amino groups in stabilizing the native structures.