(435b) Atomistic Simulations of RNA for Characterizing Folding Free Energy Surfaces

This work describes a combined parallel tempering and metadynamics technique that allows a reliable sampling of free energy landscapes of small RNAs without requiring any a priori knowledge of the system, provided that the stems fold into a canonical double-stranded helical configuration. We applied this technique to a group of closely-related 10 nucleotide tetraloops. We isolated and analyzed unfolded, folded, and misfolded populations that correspond to different free energy basins. We identified a distinct misfolded state that has a stability very close to that of the correctly folded state. This misfolded state contains a predominant population that shares the same structural features across all tetraloops studied. Our transition state analysis of the biased trajectories showed that this competitive misfolded state may be facilitating achieving the correct fold without being an essential folding intermediate. The technique is shown to be a useful asset for RNA studies at atomistic resolution as it provided substantial new insights into the role of misfolded states in RNA tetraloops. As a part of the outlook/future work, I will also discuss the practical applicability of the technique for RNAs larger than tetraloops.