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J Chem Theory Comput. 2018 Nov 27. doi: 10.1021/acs.jctc.8b00633. [Epub ahead of print]

Chemically Accurate Relative Folding Stability of RNA Hairpins from Molecular Simulations.

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Department of Biochemistry & Biophysics , University of Rochester , Rochester , New York 14642 , United States.
Center for RNA Biology , University of Rochester , Rochester , New York 14642 , United States.
Department of Biostatistics and Computational Biology , University of Rochester , Rochester , New York 14642 , United States.


To benchmark RNA force fields, we compared the folding stabilities of three 12-nucleotide hairpin stem loops estimated by simulation to stabilities determined by experiment. We used umbrella sampling and a reaction coordinate of end-to-end (5' to 3' hydroxyl oxygen) distance to estimate the free energy change of the transition from the native conformation to a fully extended conformation with no hydrogen bonds between non-neighboring bases. Each simulation was performed four times using the AMBER FF99+bsc0+χOL3 force field, and each window, spaced at 1 Å intervals, was sampled for 1 μs, for a total of 552 μs of simulation. We compared differences in the simulated free energy changes to analogous differences in free energies from optical melting experiments using thermodynamic cycles where the free energy change between stretched and random coil sequences is assumed to be sequence-independent. The differences between experimental and simulated ΔΔ G° are, on average, 0.98 ± 0.66 kcal/mol, which is chemically accurate and suggests that analogous simulations could be used predictively. We also report a novel method to identify where replica free energies diverge along a reaction coordinate, thus indicating where additional sampling would most improve convergence. We conclude by discussing methods to more economically perform these simulations.


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