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.

• MeSH
• DNA chemie   MeSH
• katalýza MeSH
• konformace nukleové kyseliny * MeSH
• počítačová simulace MeSH
• RNA chemie   MeSH
• simulace molekulární dynamiky * MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• DNA MeSH
• RNA MeSH

The sarcin-ricin RNA motif (SR motif) is one of the most prominent recurrent RNA building blocks that occurs in many different RNA contexts and folds autonomously, that is, in a context-independent manner. In this study, we combined bioinformatics analysis with explicit-solvent molecular dynamics (MD) simulations to better understand the relation between the RNA sequence and the evolutionary patterns of the SR motif. A SHAPE probing experiment was also performed to confirm the fidelity of the MD simulations. We identified 57 instances of the SR motif in a nonredundant subset of the RNA X-ray structure database and analyzed their base pairing, base-phosphate, and backbone-backbone interactions. We extracted sequences aligned to these instances from large rRNA alignments to determine the frequency of occurrence for different sequence variants. We then used a simple scoring scheme based on isostericity to suggest 10 sequence variants with a highly variable expected degree of compatibility with the SR motif 3D structure. We carried out MD simulations of SR motifs with these base substitutions. Nonisosteric base substitutions led to unstable structures, but so did isosteric substitutions which were unable to make key base-phosphate interactions. The MD technique explains why some potentially isosteric SR motifs are not realized during evolution. We also found that the inability to form stable cWW geometry is an important factor in the case of the first base pair of the flexible region of the SR motif. A comparison of structural, bioinformatics, SHAPE probing, and MD simulation data reveals that explicit solvent MD simulations neatly reflect the viability of different sequence variants of the SR motif. Thus, MD simulations can efficiently complement bioinformatics tools in studies of conservation patterns of RNA motifs and provide atomistic insight into the role of their different signature interactions.

• MeSH
• konformace nukleové kyseliny MeSH
• nukleotidové motivy MeSH
• párování bází MeSH
• RNA ribozomální chemie   metabolismus   MeSH
• RNA chemie   metabolismus   MeSH
• rozpouštědla chemie   MeSH
• simulace molekulární dynamiky MeSH
• vodíková vazba MeSH
• výpočetní biologie MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• RNA ribozomální MeSH
• RNA MeSH
• rozpouštědla MeSH

Riboswitches often occur in the 5'-untranslated regions of bacterial mRNA where they regulate gene expression. The preQ(1) riboswitch controls the biosynthesis of a hypermodified nucleoside queuosine in response to binding the queuosine metabolic intermediate. Structures of the ligand-bound and ligand-free states of the preQ(1) riboswitch from Thermoanaerobacter tengcongensis were determined recently by X-ray crystallography. We used multiple, microsecond-long molecular dynamics simulations (29 μs in total) to characterize the structural dynamics of preQ(1) riboswitches in both states. We observed different stabilities of the stem in the bound and free states, resulting in different accessibilities of the ribosome-binding site. These differences are related to different stacking interactions between nucleotides of the stem and the associated loop, which itself adopts different conformations in the bound and free states. We suggest that the loop not only serves to bind preQ(1) but also transmits information about ligand binding from the ligand-binding pocket to the stem, which has implications for mRNA accessibility to the ribosome. We explain functional results obscured by a high salt crystallization medium and help to refine regions of disordered electron density, which demonstrates the predictive power of our approach. Besides investigating the functional dynamics of the riboswitch, we have also utilized this unique small folded RNA system for analysis of performance of the RNA force field on the μs time scale. The latest AMBER parmbsc0χ(OL3) RNA force field is capable of providing stable trajectories of the folded molecule on the μs time scale. On the other hand, force fields that are not properly balanced lead to significant structural perturbations on the sub-μs time scale, which could easily lead to inappropriate interpretation of the simulation data.

• MeSH
• bakteriální RNA chemie   MeSH
• krystalografie rentgenová MeSH
• molekulární modely MeSH
• riboswitch * MeSH
• simulace molekulární dynamiky * MeSH
• Thermoanaerobacter chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• bakteriální RNA MeSH
• riboswitch * MeSH

Refinement of empirical force fields for nucleic acids requires their extensive testing using as wide range of systems as possible. However, finding unambiguous reference data is not easy. In this paper, we analyze four systems which we suggest should be included in standard portfolio of molecules to test nucleic acids force fields, namely, parallel and antiparallel stranded DNA guanine quadruplex stems, RNA quadruplex stem, and Z-DNA. We highlight parameters that should be monitored to assess the force field performance. The work is primarily based on 8.4 μs of 100-250 ns trajectories analyzed in detail followed by 9.6 μs of additional selected back up trajectories that were monitored to verify that the results of the initial analyses are correct. Four versions of the Cornell et al. AMBER force field are tested, including an entirely new parmχ(OL4) variant with χ dihedral specifically reparametrized for DNA molecules containing syn nucleotides. We test also different water models and ion conditions. While improvement for DNA quadruplexes is visible, the force fields still do not fully represent the intricate Z-DNA backbone conformation.

• Publikační typ
• časopisecké články MeSH