Physics‐based all‐atom modeling of RNA energetics and structure

Abstract

The Potential, U, is Essential: The many conformations from a simulation produce a free energy surface. The surface is realistic, if the force field, FF, is. The database of RNA sequences is exploding, but knowledge of energetics, structures, and dynamics lags behind. All-atom computational methods, such as molecular dynamics, hold promise for closing this gap. New algorithms and faster computers have accelerated progress in improving the reliability and accuracy of predictions. Currently, the methods can facilitate refinement of experimentally determined NMR and x-ray structures, but are less reliable for predictions based only on sequence. Much remains to be discovered, however, about the many molecular interactions driving RNA folding and the best way to approximate them quantitatively. The large number of parameters required means that a wide variety of experimental results will be required to benchmark force fields and different approaches. As computational methods become more reliable and accessible, they will be used by an increasing number of biologists, much as x-ray crystallography has expanded. Thus, many fundamental physical principles underlying the computational methods are described. This review presents a summary of the current state of molecular dynamics as applied to RNA. It is designed to be helpful to students, postdoctoral fellows, and faculty who are considering or starting computational studies of RNA.

Improving The Performance Of The Amber Rna Force Field By Tuning The Hydrogen-Bonding Interactions

“…Molecular dynamics (MD) simulations have become a very important tool for studies of biomolecular systems such as nucleic acids with routine access to micro-or even millisecond timescales. [1][2][3][4][5][6][7] MD simulations are often instrumental for understanding and clarifying experimental results and for obtaining a more complete picture of their biological implications.…”

Chemically Accurate Relative Folding Stability of RNA Hairpins from Molecular Simulations

“…58 Here we simulate this transition with umbrella sampling, whereby the molecule is restrained to occupy specific positions along the reaction coordinate in independent equilibrium simulations called windows. 26,70,71 The biased distributions of reaction coordinate positions are then unbiased to determine the Free Energy Curve (FEC) using the Weighted Histogram Analysis Method (WHAM) to iteratively minimize the statistical errors in overlapping regions from each simulation. 72 Simulations were run using the GPU code 73 from the AMBER 14 and AMBER 16 packages.…”

“…The force field functional form and parameters are approximations of the quantum mechanics underlying the molecular interactions. [26][27][28] There are a number of known limitations to the RNA force fields that lead to significant artifacts in the simulations when sampling is thorough. For the commonly used AMBER force field, FF99+bsc0+χ OL3 , [29][30][31] it has been observed that in simulations stable tetraloops do not retain a folded structure, 32,33 tetramers often miss contacts observed in proton NMR spectra and exhibit close contacts not observed in the spectra, 24,32 internal loops do not produce ratios of major and minor conformers similar to solution structures, 34,35 and some RNA-protein complexes are not stable for more than a microsecond.…”

“…36 It is widely believed that no available force field cheap enough to permit adequate sampling is accurate enough to fold structured RNA de novo. 26,27,37 The CHARMM 36 force field, 38 and a revised Amber force field 39 also do not correctly stabilize the native tetraloop structure nor accurately model tetramers. 32 Our recent work re-parameterizing back-bone dihedrals improves simulation accuracy for tetramers and internal loops, but not tetraloops.…”

Surprising Sequence Effects on GU Closure of Symmetric 2 × 2 Nucleotide RNA Internal Loops

“…26, 42, 61, 62 The structure of the 5′GAGU/3′UGAG internal loop 44 suggests that 2×2 nt internal loops closed by GU pairs can provide additional benchmarks for testing that balance. 40 Optical melting experiments and 1D imino proton NMR spectra of the GU closed loops studied here reveal unexpected equilibria and structures that will challenge computations.…”