With both catalytic and genetic functions, ribonucleic acid (RNA) is perhaps the most pluripotent chemical species in molecular biology, and its functions are intimately linked to its structure and dynamics. Computer simulations, and in particular atomistic molecular dynamics (MD), allow structural dynamics of biomolecular systems to be investigated with unprecedented temporal and spatial resolution. We here provide a comprehensive overview of the fast-developing field of MD simulations of RNA molecules. We begin with an in-depth, evaluatory coverage of the most fundamental methodological challenges that set the basis for the future development of the field, in particular, the current developments and inherent physical limitations of the atomistic force fields and the recent advances in a broad spectrum of enhanced sampling methods. We also survey the closely related field of coarse-grained modeling of RNA systems. After dealing with the methodological aspects, we provide an exhaustive overview of the available RNA simulation literature, ranging from studies of the smallest RNA oligonucleotides to investigations of the entire ribosome. Our review encompasses tetranucleotides, tetraloops, a number of small RNA motifs, A-helix RNA, kissing-loop complexes, the TAR RNA element, the decoding center and other important regions of the ribosome, as well as assorted others systems. Extended sections are devoted to RNA–ion interactions, ribozymes, riboswitches, and protein/RNA complexes. Our overview is written for as broad of an audience as possible, aiming to provide a much-needed interdisciplinary bridge between computation and experiment, together with a perspective on the future of the field.

Elastic network models (ENMs) are valuable and efficient tools for characterizing the collective internal dynamics of proteins based on the knowledge of their native structures. The increasing evidence that the biological functionality of RNAs is often linked to their innate internal motions poses the question of whether ENM approaches can be successfully extended to this class of biomolecules. This issue is tackled here by considering various families of elastic networks of increasing complexity applied to a representative set of RNAs. The fluctuations predicted by the alternative ENMs are stringently validated by comparison against extensive molecular dynamics simulations and SHAPE experiments. We find that simulations and experimental data are systematically best reproduced by either an all-atom or a three-beads-per-nucleotide representation (sugar-base-phosphate), with the latter arguably providing the best balance of accuracy and computational complexity.

RNA molecules are highly dynamic systems characterized by a complex interplay between sequence, structure, dynamics, and function. Molecular simulations can potentially provide powerful insights into the nature of these relationships. The analysis of structures and molecular trajectories of nucleic acids can be nontrivial because it requires processing very high-dimensional data that are not easy to visualize and interpret. Here we introduce Barnaba, a Python library aimed at facilitating the analysis of nucleic acid structures and molecular simulations. The software consists of a variety of analysis tools that allow the user to (i) calculate distances between three-dimensional structures using different metrics, (ii) backcalculate experimental data from three-dimensional structures, (iii) perform cluster analysis and dimensionality reductions, (iv) search three-dimensional motifs in PDB structures and trajectories, and (v) construct elastic network models for nucleic acids and nucleic acids-protein complexes. In addition, Barnaba makes it possible to calculate torsion angles, pucker conformations, and to detect base-pairing/base-stacking interactions. Barnaba produces graphics that conveniently visualize both extended secondary structure and dynamics for a set of molecular conformations. The software is available as a command-line tool as well as a library, and supports a variety of file formats such as PDB, dcd, and xtc files. Source code, documentation, and examples are freely available at https://github.com/srnas/barnaba under GNU GPLv3 license.

Nowadays different experimental techniques, such as single molecule or relaxation experiments, can provide dynamic properties of biomolecular systems, but the amount of detail obtainable with these methods is often limited in terms of time or spatial resolution. Here we use state-of-the-art computational techniques, namely atomistic molecular dynamics and Markov state models, to provide insight into the rapid dynamics of short RNA oligonucleotides, in order to elucidate the kinetics of stacking interactions. Analysis of multiple microsecond-long simulations indicates that the main relaxation modes of such molecules can consist of transitions between alternative folded states, rather than between random coils and native structures. After properly removing structures that are artificially stabilized by known inaccuracies of the current RNA AMBER force field, the kinetic properties predicted are consistent with the timescales of previously reported relaxation experiments.