RNA folding pathways from all-atom simulations with a variationally improved history-dependent bias

Atomically detailed simulations of RNA folding have proven very challenging in view of the difficulties of developing realistic force fields and the intrinsic computational complexity of sampling rare conformational transitions. As a step forward in tackling these issues, we extend to RNA an enhanced path-sampling method previously successfully applied to proteins. In this scheme, the information about the RNA's native structure is harnessed by a soft history-dependent biasing force promoting the generation of productive folding trajectories in an all-atom force field with explicit solvent. A rigorous variational principle is then applied to minimize the effect of the bias. Here, we report on an application of this method to RNA molecules from 20 to 47 nucleotides long and increasing topological complexity. By comparison with analog simulations performed on small proteins with similar size and architecture, we show that the RNA folding landscape is significantly more frustrated, even for relatively small chains with a simple topology. The predicted RNA folding mechanisms are found to be consistent with the available experiments and some of the existing coarse-grained models. Due to its computational performance, this scheme provides a promising platform to efficiently gather atomistic RNA folding trajectories, thus retain the information about the chemical composition of the sequence.

Automated summary

By applying an enhanced path-sampling method to RNA, we successfully simulate the folding process and resolve the challenges of developing realistic force fields and sampling rare conformational transitions. The folding landscape of RNA is found to be more frustrated compared to small proteins with similar size and architecture. The predicted folding mechanisms of RNA are consistent with experiments and existing models. This method provides a promising platform to accurately study atomistic RNA folding trajectories and preserve sequence information.