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 chemistry   MeSH
• Catalysis MeSH
• Nucleic Acid Conformation * MeSH
• Computer Simulation MeSH
• RNA chemistry   MeSH
• Molecular Dynamics Simulation * MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• DNA MeSH
• RNA MeSH

We provide theoretical predictions of the intrinsic stability of different arrangements of guanine quadruplex (G-DNA) stems. Most computational studies of nucleic acids have applied Molecular Mechanics (MM) approaches using simple pairwise-additive force fields. The principle limitation of such calculations is the highly approximate nature of the force fields. In this study, we for the first time apply accurate QM computations (DFT-D3 with large atomic orbital basis sets) to essentially complete DNA building blocks, seven different folds of the cation-stabilized two-quartet G-DNA stem, each having more than 250 atoms. The solvent effects are approximated by COSMO continuum solvent. We reveal sizable differences between MM and QM descriptions of relative energies of different G-DNA stems, which apparently reflect approximations of the DNA force field. Using the QM energy data, we propose correction to earlier free energy estimates of relative stabilities of different parallel, hybrid, and antiparallel G-stem folds based on classical simulations. The new energy ranking visibly improves the agreement between theory and experiment. We predict the 5'-anti-anti-3' GpG dinucleotide step to be the most stable one, closely followed by the 5'-syn-anti-3' step. The results are in good agreement with known experimental structures of 2-, 3-, and 4-quartet G-DNA stems. Besides providing specific results for G-DNA, our study highlights basic limitations of force field modeling of nucleic acids. Although QM computations have their own limitations, mainly the lack of conformational sampling and the approximate description of the solvent, they can substantially improve the quality of calculations currently relying exclusively on force fields.

• MeSH
• DNA chemistry   MeSH
• G-Quadruplexes * MeSH
• Guanine chemistry   MeSH
• Quantum Theory * MeSH
• Models, Molecular MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Names of Substances
• DNA MeSH
• Guanine MeSH

In this feature article, we provide a side-by-side introduction for two research fields: quantum chemical calculations of molecular interaction in nucleic acids and RNA structural bioinformatics. Our main aim is to demonstrate that these research areas, while largely separated in contemporary literature, have substantial potential to complement each other that could significantly contribute to our understanding of the exciting world of nucleic acids. We identify research questions amenable to the combined application of modern ab initio methods and bioinformatics analysis of experimental structures while also assessing the limitations of these approaches. The ultimate aim is to attain valuable physicochemical insights regarding the nature of the fundamental molecular interactions and how they shape RNA structures, dynamics, function, and evolution.

• MeSH
• Nucleic Acid Conformation MeSH
• Quantum Theory * MeSH
• Nucleic Acids chemistry   MeSH
• RNA chemistry   MeSH
• Computational Biology * MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Names of Substances
• Nucleic Acids MeSH
• RNA MeSH

We describe a novel, fundamental property of nucleobase structure, namely, pyramidilization at the N1/9 sites of purine and pyrimidine bases. Through a combined analyses of ultra-high-resolution X-ray structures of both oligonucleotides extracted from the Nucleic Acid Database and isolated nucleotides and nucleosides from the Cambridge Structural Database, together with a series of quantum chemical calculations, molecular dynamics (MD) simulations, and published solution nuclear magnetic resonance (NMR) data, we show that pyramidilization at the glycosidic nitrogen is an intrinsic property. This property is common to isolated nucleosides and nucleotides as well as oligonucleotides-it is also common to both RNA and DNA. Our analysis suggests that pyramidilization at N1/9 sites depends in a systematic way on the local structure of the nucleoside. Of note, the pyramidilization undergoes stereo-inversion upon reorientation of the glycosidic bond. The extent of the pyramidilization is further modulated by the conformation of the sugar ring. The observed pyramidilization is more pronounced for purine bases, while for pyrimidines it is negligible. We discuss how the assumption of nucleic acid base planarity can lead to systematic errors in determining the conformation of nucleotides from experimental data and from unconstrained MD simulations.

• MeSH
• Deoxyadenosines chemistry   MeSH
• Deoxycytidine chemistry   MeSH
• Nitrogen chemistry   MeSH
• Crystallography, X-Ray MeSH
• Nuclear Magnetic Resonance, Biomolecular MeSH
• Oligonucleotides chemistry   MeSH
• Computer Simulation MeSH
• Purine Nucleosides chemistry   MeSH
• Purine Nucleotides chemistry   MeSH
• Purines chemistry   MeSH
• Pyrimidine Nucleosides chemistry   MeSH
• Pyrimidine Nucleotides chemistry   MeSH
• Pyrimidines chemistry   MeSH
• Carbohydrates chemistry   MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 2'-deoxyadenosine MeSH Browser
• Deoxyadenosines MeSH
• Deoxycytidine MeSH
• Nitrogen MeSH
• Oligonucleotides MeSH
• Purine Nucleosides MeSH
• Purine Nucleotides MeSH
• Purines MeSH
• Pyrimidine Nucleosides MeSH
• Pyrimidine Nucleotides MeSH
• Pyrimidines MeSH
• Carbohydrates MeSH

Guanine-adenine (GA) base pairs play important roles in determining the structure, dynamics, and stability of RNA. In RNA internal loops, GA base pairs often occur in tandem arrangements and their structure is context and sequence dependent. Calculations reported here test the thermodynamic integration (TI) approach with the amber99 force field by comparing computational predictions of free energy differences with the free energy differences expected on the basis of NMR determined structures of the RNA motifs (5'-GCGGACGC-3')(2), (5'-GCiGGAiCGC-3')(2), (5'-GGCGAGCC-3')(2), and (5'-GGiCGAiGCC-3')(2). Here, iG and iC denote isoguanosine and isocytidine, which have amino and carbonyl groups transposed relative to guanosine and cytidine. The NMR structures show that the GA base pairs adopt either imino (cis Watson-Crick/Watson-Crick A-G) or sheared (trans Hoogsteen/Sugar edge A-G) conformations depending on the identity and orientation of the adjacent base pair. A new mixing function for the TI method is developed that allows alchemical transitions in which atoms can disappear in both the initial and final states. Unrestrained calculations gave DeltaG degrees values 2-4 kcal/mol different from expectations based on NMR data. Restraining the structures with hydrogen bond restraints did not improve the predictions. Agreement with NMR data was improved by 0.7 to 1.5 kcal/mol, however, when structures were restrained with weak positional restraints to sample around the experimentally determined NMR structures. The amber99 force field was modified to partially include pyramidalization effects of the unpaired amino group of guanosine in imino GA base pairs. This provided little or no improvement in comparisons with experiment. The marginal improvement is observed when the structure has potential cross-strand out-of-plane hydrogen bonding with the G amino group. The calculations using positional restraints and a nonplanar amino group reproduce the signs of DeltaG degrees from the experimental results and are, thus, capable of providing useful qualitative insights complementing the NMR experiments. Decomposition of the terms in the calculations reveals that the dominant terms are from electrostatic and interstrand interactions other than hydrogen bonds in the base pairs. The results suggest that a better description of the backbone is key to reproducing the experimental free energy results with computational free energy predictions.

• Publication type
• Journal Article MeSH

Explicit solvent molecular dynamics (MD) simulations were carried out for three RNA kissing-loop complexes. The theoretical structure of two base pairs (2 bp) complex of H3 stem-loop of Moloney murine leukemia virus agrees with the NMR structure with modest violations of few NMR restraints comparable to violations present in the NMR structure. In contrast to the NMR structure, however, MD shows relaxed intermolecular G-C base pairs. The core region of the kissing complex forms a cation-binding pocket with highly negative electrostatic potential. The pocket shows nanosecond-scale breathing motions coupled with oscillations of the whole molecule. Additional simulations were carried out for 6 bp kissing complexes of the DIS HIV-1 subtypes A and B. The simulated structures agree well with the X-ray data. The subtype B forms a novel four-base stack of bulged-out adenines. Both 6 bp kissing complexes have extended cation-binding pockets in their central parts. While the pocket of subtype A interacts with two hexacoordinated Mg2+ ions and one sodium ion, pocket of subtype B is filled with a string of three delocalized Na+ ions with residency times of individual cations 1-2 ns. The 6 bp complexes show breathing motions of the cation-binding pockets and loop major grooves.

• MeSH
• HIV-1 genetics   MeSH
• Magnesium metabolism   MeSH
• Cations metabolism   MeSH
• Nucleic Acid Conformation * MeSH
• Models, Molecular MeSH
• Nuclear Magnetic Resonance, Biomolecular MeSH
• RNA, Viral chemistry   genetics   metabolism   MeSH
• Sodium metabolism   MeSH
• Binding Sites MeSH
• Moloney murine leukemia virus genetics   MeSH
• Water chemistry   MeSH
• Hydrogen Bonding MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Magnesium MeSH
• Cations MeSH
• RNA, Viral MeSH
• Sodium MeSH
• Water MeSH