We report the folding thermodynamics of ccUUCGgg and ccGAGAgg RNA tetraloops using atomistic molecular dynamics simulations. We obtain a previously unreported estimation of the folding free energy using parallel tempering in combination with well-tempered metadynamics. A key ingredient is the use of a recently developed metric distance, eRMSD, as a biased collective variable. We find that the native fold of both tetraloops is not the global free energy minimum using the AmberχOL3 force field. The estimated folding free energies are 30.2 ± 0.5 kJ/mol for UUCG and 7.5 ± 0.6 kJ/mol for GAGA, in striking disagreement with experimental data. We evaluate the viability of all possible one-dimensional backbone force field corrections. We find that disfavoring the gauche+ region of α and ζ angles consistently improves the existing force field. The level of accuracy achieved with these corrections, however, cannot be considered sufficient by judging on the basis of available thermodynamic data and solution experiments.

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

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

SISSA International School for Advanced Studies 265 Via Bonomea 1 34136 Trieste Italy

J Phys Chem Lett. 2018 Apr 5;9(7):1674-1675. doi: 10.1021/acs.jpclett.8b00754. PubMed

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