RNA hairpin loops represent important RNA motifs with indispensable biological functions in RNA folding and tertiary interactions, with the 5'-UNCG-3' and 5'-GNRA-3' families being the most abundant. Molecular dynamics simulations represent a powerful method to investigate the structure, folding, and function of these tetraloops (TLs), but previous AMBER force fields were unable to maintain even the native structure of small TL RNAs. Here, we have used Replica Exchange Molecular Dynamics (REMD) with our recent reparameterization of AMBER RNA force field to study the folding of RNA hairpins containing representatives UNCG and GNRA TLs. We find that in each case, we are able to reach conformations within 2 Å of the native structure, in contrast to results with earlier force fields. Although we find that the REMD simulation runs of a total of ∼19 μs (starting from both folded and unfolded state) in duration for each TL are still far from obtaining a representative equilibrium distribution at each temperature, we are nonetheless able to map the stable species on the folding energy landscape. The qualitative picture we obtain is consistent with experimental studies of RNA folding in that there are a number of stable on- and off-pathway intermediates en route to the native state. In particular, we have identified a misfolded-bulged state of GNRA TL, which shares many structural features with the X-ray structure of GNRA TL in the complex with restrictocin, namely the bulged out AL4 base. Since this is the same conformation observed in the complex of the TL with restrictocin, we argue that GNRA TL is able to bind restrictocin via a "conformational selection" mechanism, with the RL3 and AL4 bases being exposed to the solvent prior to binding. In addition we have identified a misfolded-anti state of UUCG TL, which is structurally close to the native state except that the GL4 nucleotide is in an anti-conformation instead of the native syn. Our data suggest that the UUCG misfolded-anti state may be a kinetic trap for the UUCG folding.

CEITEC Central European Institute of Technology Masaryk University Campus Bohunice Kamenice 5 625 00 Brno Czech Republic

Institute of Biophysics Academy of Sciences of the Czech Republic Kralovopolska 135 612 65 Brno Czech Republic

Laboratory of Chemical Physics National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health Bethesda Maryland 20892 0520 United States

Regional Centre of Advanced Technologies and Materials Department of Physical Chemistry Faculty of Science Palacky University Olomouc 17 listopadu 12 771 46 Olomouc Czech Republic

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