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. © 2016 American Chemical Society.

Free Energy Landscape of GAGA and UUCG RNA Tetraloops

Bottaro, Sandro;
2016

Abstract

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. © 2016 American Chemical Society.
Bioinformatics
Molecular dynamics
RNA
Thermodynamics
Atomistic molecular dynamics simulations
Collective variables
Energy minima
Folding thermodynamics
Free energy landscape
Metric distances
Parallel tempering
Thermodynamic data
Free energy
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11699/60568
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