We report the unbiased folding of two hyper-stable RNA tetraloops to less than 1 � RMSD from their experimentally determined structures using molecular dynamics simulations started from the unfolded state. RNA tetraloops with loop sequences UUCG, and GCAA are hyper-stable due to the formation of non-canonical loop-stabilizing interactions, all of which are faithfully reproduced to angstrom-level accuracy in replica-exchange molecular dynamics simulations including explicit solvent and ion molecules. This is accomplished using new RNA parameters in which existing biases that favor rigid, highly stacked conformations are ameliorated in order to accurately capture the inherent flexibility of single-stranded RNA loops, accurate base stacking energetics, and purine anti-syn interconversions. In a departure from traditional quantum chemistry-centric approaches to force-field optimization, our parameters are calibrated directly from thermodynamic and kinetic measurements of intra and inter-nucleotide structural transitions.This work is supported by NSF MCB 1050966 and by an NIH Postdoctoral Fellowship to AAC.

High resolution reversible folding simulations of hyperstable RNA tetraloops

246th National Meeting (2013)

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