Improved Force Field Parameters Lead to a Better Description of RNA Structure

Bergonzo, Christina; Cheatham, Thomas E.

doi:10.1021/acs.jctc.5b00444

Cited by 137 publications

(262 citation statements)

References 27 publications

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“…Indeed, the OPC water model has been designed specifically to improve the agreement between calculated and experimental solvation free energies for organic compounds. Also, in line with our results are simulation studies by Bergonzo and Cheetham (45) on small RNA molecules that indicated a much better agreement of sampled short RNA conformations with experimental results when using the OPC versus TIP3P or TIP4PEw water models (mostly due to incorrect stacking for the latter models).…”

Section: Resultssupporting

confidence: 91%

Free energy analysis and mechanism of base pair stacking in nicked DNA

Häse

Zacharias

2016

Nucleic Acids Res

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The equilibrium of stacked and unstacked base pairs is of central importance for all nucleic acid structure formation processes. The stacking equilibrium is influenced by intramolecular interactions between nucleosides but also by interactions with the solvent. Realistic simulations on nucleic acid structure formation and flexibility require an accurate description of the stacking geometry and stability and its sequence dependence. Free energy simulations have been conducted on a series of double stranded DNA molecules with a central strand break (nick) in one strand. The change in free energy upon unstacking was calculated for all ten possible base pair steps using umbrella sampling along a center-of-mass separation coordinate and including a comparison of different water models. Comparison to experimental studies indicates qualitative agreement of the stability order but a general overestimation of base pair stacking interactions in the simulations. A significant dependence of calculated nucleobase stacking free energies on the employed water model was observed with the tendency of stacking free energies being more accurately reproduced by more complex water models. The simulation studies also suggest a mechanism of stacking/unstacking that involves significant motions perpendicular to the reaction coordinate and indicate that the equilibrium nicked base pair step may slightly differ from regular B-DNA geometry in a sequence-dependent manner.

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Section: Resultssupporting

confidence: 91%

Free energy analysis and mechanism of base pair stacking in nicked DNA

Häse

Zacharias

2016

Nucleic Acids Res

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“…We additionally envisage the possibility of testing recent corrections to the Van der Waals parameters 15,45 in conjunction with more accurate water models. 46,47 Sports of the Czech Republic (JS and PB). JS acknowledges support by Praemium Academiae.…”

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confidence: 99%

Free Energy Landscape of GAGA and UUCG RNA Tetraloops

Bottaro

Banáš

Šponer

et al. 2016

J. Phys. Chem. Lett.

179

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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 Amber\c{hi}OL3 force field. The estimated folding free energies are 30.2kJ/mol for UUCG and 7.5 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 {\alpha} and {\zeta} 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.Comment: Journal of Physical Chemistry Letters (2016

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“…19,20 All calculations were performed using the parm99 force field 21,22 supplemented with the bsc0 23 and chiOL3 24,25 modifications for RNA; some control simulations were performed with a local experimental RNA version of the parmbsc1 forcefield. 26 Electroneutrality was achieved by adding K + and extra K + Cl -to generate a 150 mM concentration (taking Dang's parameters [27][28][29] to represent ions). US calculations were performed to determine the free energy associated with S↔N conformational transition in a protein-RNA (MIWI PAZ domain bound to RNA; PDB ID 2XFM model 6) complex in the wild type, where Lys316 is in the vicinity of O2', and a mutant protein, where Lys316 is substituted by an alanine (K316A mutant).…”

Section: Classical Simulationsmentioning

confidence: 99%

“…This correction to the Lennard Jones potential isS9 based on the AMBER parameters revision for organic phosphates proposed by 270 Steinbrecher et al, 28 which was recently shown to improve the description of RNA 271 tetranucleotides. 29 In the present work, instead of including a general Lennard-Jones 272 correction affecting the interaction between the phosphate oxygen atoms and all other 273 atoms in the system, the specific terms affecting only the atoms mentioned above were 274 corrected (see Supplementary Methods 5 section for the parmed.py script). The Kappa 275 torsion parameters were fitted as before but using the parmbsc0chiOL3vdW H1-CT-OK-HO=0 276 pmf for the MM level reference (see Supplementary Figure 7).…”

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confidence: 99%

Small Details Matter: The 2′-Hydroxyl as a Conformational Switch in RNA

et al. 2016

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While DNA is mostly a primary carrier of genetic information and displays a regular duplex structure, RNA can form very complicated and conserved 3D structures displaying a large variety of functions, such as being an intermediary carrier of the genetic information, translating such information into the protein machinery of the cell, or even acting as a chemical catalyst. At the base of such functional diversity is the subtle balance between different backbone, nucleobase, and ribose conformations, finely regulated by the combination of hydrogen bonds and stacking interactions. Although an apparently simple chemical modification, the presence of the 2'OH in RNA has a profound effect in the ribonucleotide conformational balance, adding an extra layer of complexity to the interactions network in RNA. In the present work, we have combined database analysis with extensive molecular dynamics, quantum mechanics, and hybrid QM/MM simulations to provide direct evidence on the dramatic impact of the 2'OH conformation on sugar puckering. Calculations provide evidence that proteins can modulate the 2'OH conformation to drive sugar repuckering, leading then to the formation of bioactive conformations. In summary, the 2'OH group seems to be a primary molecular switch contributing to specific protein-RNA recognition.

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Improved Force Field Parameters Lead to a Better Description of RNA Structure

Cited by 137 publications

References 27 publications

Free energy analysis and mechanism of base pair stacking in nicked DNA

Free energy analysis and mechanism of base pair stacking in nicked DNA

Free Energy Landscape of GAGA and UUCG RNA Tetraloops

Small Details Matter: The 2′-Hydroxyl as a Conformational Switch in RNA

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