Adjusting the energy profile for CH–O interactions leads to improved stability of RNA stem-loop structures in MD simulations

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The role of RNA in biology continues to grow but insight into important aspects of RNA behavior is lacking, such as dynamic structural ensembles in different environments, how flexibility is coupled to function, and how function might be modulated by small molecule binding. In the case of proteins, much progress in these areas has been made by complementing experiments with atomistic simulations, but RNA simulation methods and force fields are less mature. It remains challenging to generate stable RNA simulations, even for small systems where well-defined, thermostable structures have been established by experiments. Many different aspects of RNA energetics have been adjusted in force fields, seeking improvements that are transferable across a variety of RNA structural motifs. In this work, we explore the role of weak CH…O interactions, which are ubiquitous in RNA structure but have received less attention in RNA force field development. By comparing data extracted from high-resolution RNA crystal structures to energy profiles from quantum mechanics and force field calculations, we demonstrate that CH…O interactions are overly repulsive in the widely-used Amber RNA force fields. We developed a simple, targeted adjustment of CH…O repulsion that leaves the remainder of the force field unchanged. We then tested the standard and modified force fields using MD simulations with explicit water and salt, amassing over 300 μsec of data for multiple RNA systems containing important features such as presence of loops, base stacking interactions as well as canonical and non-canonical base pairing. Our results demonstrate that the standard force fields lead to reproducible unfolding of the NMR-based structures, as has been reported by others. Including our CH…O adjustment in an otherwise identical protocol dramatically improves the outcome, leading to stable simulations for all RNA systems tested.

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