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 RNA hairpin loops represent important RNA topologies with indispensable biological functions in RNA folding and tertiary interactions. 5'-UNCG-3' and 5'-GNRA-3' RNA tetraloops are the most important classes of RNA hairpin loops. Both tetraloops are highly structured with characteristic signature three-dimensional features and are recurrently seen in functional RNAs and ribonucleoprotein particles. Explicit solvent molecular dynamics (MD) simulation is a computational technique which can efficiently complement the experimental data and provide unique structural dynamics information on the atomic scale. Nevertheless, the outcome of simulations is often compromised by imperfections in the parametrization of simplified pairwise additive empirical potentials referred to also as force fields. We have pointed out in several recent studies that a force field description of single-stranded hairpin segments of nucleic acids may be particularly challenging for the force fields. In this paper, we report a critical assessment of a broad set of MD simulations of UUCG, GAGA, and GAAA tetraloops using various force fields. First, we utilized the three widely used variants of Cornell et al. (AMBER) force fields known as ff94, ff99, and ff99bsc0. Some simulations were also carried out with CHARMM27. The simulations reveal several problems which show that these force fields are not able to retain all characteristic structural features (structural signature) of the studied tetraloops. Then we tested four recent reparameterizations of glycosidic torsion of the Cornell et al. force field (two of them being currently parametrized in our laboratories). We show that at least some of the new versions show an improved description of the tetraloops, mainly in the syn glycosidic torsion region of the UNCG tetraloop. The best performance is achieved in combination with the bsc0 parametrization of the α/γ angles. Another critically important region to properly describe RNA molecules is the anti/high-anti region of the glycosidic torsion, where there are significant differences among the tested force fields. The tetraloop simulations are complemented by simulations of short A-RNA stems, which are especially sensitive to an appropriate description of the anti/high-anti region. While excessive accessibility of the high-anti region converts the A-RNA into a senseless "ladder-like" geometry, excessive penalization of the high-anti region shifts the simulated structures away from typical A-RNA geometry to structures with a visibly underestimated inclination of base pairs with respect to the helical axis.

• Publikační typ
• časopisecké články MeSH

Explicit solvent molecular dynamics (MD) simulations were carried out for sarcin-ricin domain (SRD) motifs from 23S (Escherichia coli) and 28S (rat) rRNAs. The SRD motif consists of GAGA tetraloop, G-bulged cross-strand A-stack, flexible region and duplex part. Detailed analysis of the overall dynamics, base pairing, hydration, cation binding and other SRD features is presented. The SRD is surprisingly static in multiple 25 ns long simulations and lacks any non-local motions, with root mean square deviation (r.m.s.d.) values between averaged MD and high-resolution X-ray structures of 1-1.4 A. Modest dynamics is observed in the tetraloop, namely, rotation of adenine in its apex and subtle reversible shift of the tetraloop with respect to the adjacent base pair. The deformed flexible region in low-resolution rat X-ray structure is repaired by simulations. The simulations reveal few backbone flips, which do not affect positions of bases and do not indicate a force field imbalance. Non-Watson-Crick base pairs are rigid and mediated by long-residency water molecules while there are several modest cation-binding sites around SRD. In summary, SRD is an unusually stiff rRNA building block. Its intrinsic structural and dynamical signatures seen in simulations are strikingly distinct from other rRNA motifs such as Loop E and Kink-turns.

• MeSH
• endoribonukleasy metabolismus   MeSH
• Escherichia coli genetika   MeSH
• fungální proteiny metabolismus   MeSH
• kationty chemie   MeSH
• konformace nukleové kyseliny MeSH
• krysa rodu Rattus MeSH
• krystalografie rentgenová MeSH
• molekulární modely * MeSH
• párování bází MeSH
• počítačová simulace MeSH
• ricin metabolismus   MeSH
• RNA ribozomální 23S chemie   metabolismus   MeSH
• RNA ribozomální 28S chemie   metabolismus   MeSH
• sacharidy chemie   MeSH
• vazebná místa MeSH
• voda chemie   MeSH
• vodíková vazba MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• alpha-sarcin MeSH Prohlížeč
• endoribonukleasy MeSH
• fungální proteiny MeSH
• kationty MeSH
• ricin MeSH
• RNA ribozomální 23S MeSH
• RNA ribozomální 28S MeSH
• sacharidy MeSH
• voda MeSH