Hydrogen bonding between nucleobases is a crucial noncovalent interaction for life on Earth. Canonical nucleobases form base pairs according to two main geometries: Watson-Crick pairing, which enables the static functions of nucleic acids, such as the storing of genetic information; and Hoogsteen pairing, which facilitates the dynamic functions of these biomacromolecules. This precisely tuned system can be affected by oxidation or substitution of nucleobases, leading to changes in their hydrogen-bonding patterns. This paper presents an investigation into the intermolecular interactions of various 8-substituted purine derivatives with their hydrogen-bonding partners. The systems were analyzed using nuclear magnetic resonance spectroscopy and density functional theory calculations. Our results demonstrate that the stability of hydrogen-bonded complexes, or base pairs, depends primarily on the number of intermolecular H-bonds and their donor-acceptor alternation. No strong preferences for a particular geometry, either Watson-Crick or Hoogsteen, were found.

• Publication type
• Journal Article MeSH

We evaluate the performance of the most widely used wavefunction, density functional theory, and semiempirical methods for the description of noncovalent interactions in a set of larger, mostly dispersion-stabilized noncovalent complexes (the L7 data set). The methods tested include MP2, MP3, SCS-MP2, SCS(MI)-MP2, MP2.5, MP2.X, MP2C, DFT-D, DFT-D3 (B3-LYP-D3, B-LYP-D3, TPSS-D3, PW6B95-D3, M06-2X-D3) and M06-2X, and semiempirical methods augmented with dispersion and hydrogen bonding corrections: SCC-DFTB-D, PM6-D, PM6-DH2 and PM6-D3H4. The test complexes are the octadecane dimer, the guanine trimer, the circumcoronene…adenine dimer, the coronene dimer, the guanine-cytosine dimer, the circumcoronene…guanine-cytosine dimer, and an amyloid fragment trimer containing phenylalanine residues. The best performing method is MP2.5 with relative root mean square deviation (rRMSD) of 4 %. It can thus be recommended as an alternative to the CCSD(T)/CBS (alternatively QCISD(T)/CBS) benchmark for molecular systems which exceed current computational capacity. The second best non-DFT method is MP2C with rRMSD of 8 %. A method with the most favorable "accuracy/cost" ratio belongs to the DFT family: BLYP-D3, with an rRMSD of 8 %. Semiempirical methods deliver less accurate results (the rRMSD exceeds 25 %). Nevertheless, their absolute errors are close to some much more expensive methods such as M06-2X, MP2 or SCS(MI)-MP2, and thus their price/performance ratio is excellent.

• Publication type
• Journal Article 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

The article reviews the application of biomolecular simulation methods to understand the structure, dynamics and interactions of nucleic acids with a focus on explicit solvent molecular dynamics simulations of guanine quadruplex (G-DNA and G-RNA) molecules. While primarily dealing with these exciting and highly relevant four-stranded systems, where recent and past simulations have provided several interesting results and novel insight into G-DNA structure, the review provides some general perspectives on the applicability of the simulation techniques to nucleic acids.

• MeSH
• DNA chemistry   MeSH
• G-Quadruplexes * MeSH
• Guanine chemistry   MeSH
• Nucleic Acid Conformation MeSH
• Ligands MeSH
• RNA chemistry   MeSH
• Solvents chemistry   MeSH
• Molecular Dynamics Simulation * MeSH
• Telomere chemistry   MeSH
• Hydrogen Bonding MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review 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
• Ligands MeSH
• RNA MeSH
• Solvents MeSH

Folded RNA molecules are shaped by an astonishing variety of highly conserved noncanonical molecular interactions and backbone topologies. The dinucleotide platform is a widespread recurrent RNA modular building submotif formed by the side-by-side pairing of bases from two consecutive nucleotides within a single strand, with highly specific sequence preferences. This unique arrangement of bases is cemented by an intricate network of noncanonical hydrogen bonds and facilitated by a distinctive backbone topology. The present study investigates the gas-phase intrinsic stabilities of the three most common RNA dinucleotide platforms - 5'-GpU-3', ApA, and UpC - via state-of-the-art quantum-chemical (QM) techniques. The mean stability of base-base interactions decreases with sequence in the order GpU > ApA > UpC. Bader's atoms-in-molecules analysis reveals that the N2(G)…O4(U) hydrogen bond of the GpU platform is stronger than the corresponding hydrogen bonds in the other two platforms. The mixed-pucker sugar-phosphate backbone conformation found in most GpU platforms, in which the 5'-ribose sugar (G) is in the C2'-endo form and the 3'-sugar (U) in the C3'-endo form, is intrinsically more stable than the standard A-RNA backbone arrangement, partially as a result of a favorable O2'…O2P intra-platform interaction. Our results thus validate the hypothesis of Lu et al. (Lu Xiang-Jun, et al. Nucleic Acids Res. 2010, 38, 4868-4876), that the superior stability of GpU platforms is partially mediated by the strong O2'…O2P hydrogen bond. In contrast, ApA and especially UpC platform-compatible backbone conformations are rather diverse and do not display any characteristic structural features. The average stabilities of ApA and UpC derived backbone conformers are also lower than those of GpU platforms. Thus, the observed structural and evolutionary patterns of the dinucleotide platforms can be accounted for, to a large extent, by their intrinsic properties as described by modern QM calculations. In contrast, we show that the dinucleotide platform is not properly described in the course of atomistic explicit-solvent simulations. Our work also gives methodological insights into QM calculations of experimental RNA backbone geometries. Such calculations are inherently complicated by rather large data and refinement uncertainties in the available RNA experimental structures, which often preclude reliable energy computations.

• Publication type
• Journal Article 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

Hybrid QM/MM methods combine the rigor of quantum mechanical (QM) calculations with the low computational cost of empirical molecular mechanical (MM) treatment allowing to capture dynamic properties to probe critical atomistic details of enzyme reactions. Catalysis by RNA enzymes (ribozymes) has only recently begun to be addressed with QM/MM approaches and is thus still a field under development. This review surveys methodology as well as recent advances in QM/MM applications to RNA mechanisms, including those of the HDV, hairpin, and hammerhead ribozymes, as well as the ribosome. We compare and correlate QM/MM results with those from QM and/or molecular dynamics (MD) simulations, and discuss scope and limitations with a critical eye on current shortcomings in available methodologies and computer resources. We thus hope to foster mutual appreciation and facilitate collaboration between experimentalists and theorists to jointly advance our understanding of RNA catalysis at an atomistic level.

• MeSH
• Biophysics methods   MeSH
• Phosphates chemistry   MeSH
• Phosphorylation MeSH
• Magnesium chemistry   MeSH
• Catalysis MeSH
• Nucleic Acid Conformation MeSH
• Quantum Theory MeSH
• Humans MeSH
• Models, Molecular MeSH
• Computer Simulation MeSH
• Ribosomes chemistry   MeSH
• RNA, Catalytic chemistry   MeSH
• RNA, Viral chemistry   MeSH
• RNA chemistry   MeSH
• Software MeSH
• Check Tag
• Humans 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
• Phosphates MeSH
• hammerhead ribozyme MeSH Browser
• Magnesium MeSH
• RNA, Catalytic MeSH
• RNA, Viral MeSH
• RNA MeSH

This review provides a critical assessment of the advantages and limitations of modeling methods available for guanine quadruplex (G-DNA) molecules. We characterize the relations of simulations to the experimental techniques and explain the actual meaning and significance of the results. The following aspects are discussed: pair-additive approximation of the empirical force fields, sampling limitations stemming from the simulation time and accuracy of description of base stacking, H-bonding, sugar-phosphate backbone and ions by force fields. Several methodological approaches complementing the classical explicit solvent molecular dynamics simulations are commented on, including enhanced sampling methods, continuum solvent methods, free energy calculations and gas phase simulations. The successes and pitfalls of recent simulation studies of G-DNA are demonstrated on selected results, including studies of cation interactions and dynamics of G-DNA stems, studies of base substitutions (inosine, thioguanine and mixed tetrads), analysis of possible kinetic intermediates in folding pathway of a G-DNA stem and analysis of loop regions of G-DNA molecules.

• MeSH
• DNA chemistry   MeSH
• G-Quadruplexes * MeSH
• Guanine chemistry   MeSH
• Ligands MeSH
• Models, Molecular MeSH
• Computer Simulation MeSH
• Thermodynamics MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• DNA MeSH
• Guanine MeSH
• Ligands MeSH

Explicit solvent and counterion molecular dynamics simulations have been carried out for a total of >80 ns on the bacterial and spinach chloroplast 5S rRNA Loop E motifs. The Loop E sequences form unique duplex architectures composed of seven consecutive non-Watson-Crick basepairs. The starting structure of spinach chloroplast Loop E was modeled using isostericity principles, and the simulations refined the geometries of the three non-Watson-Crick basepairs that differ from the consensus bacterial sequence. The deep groove of Loop E motifs provides unique sites for cation binding. Binding of Mg(2+) rigidifies Loop E and stabilizes its major groove at an intermediate width. In the absence of Mg(2+), the Loop E motifs show an unprecedented degree of inner-shell binding of monovalent cations that, in contrast to Mg(2+), penetrate into the most negative regions inside the deep groove. The spinach chloroplast Loop E shows a marked tendency to compress its deep groove compared with the bacterial consensus. Structures with a narrow deep groove essentially collapse around a string of Na(+) cations with long coordination times. The Loop E non-Watson-Crick basepairing is complemented by highly specific hydration sites ranging from water bridges to hydration pockets hosting 2 to 3 long-residing waters. The ordered hydration is intimately connected with RNA local conformational variations.

• MeSH
• RNA, Bacterial chemistry   MeSH
• Base Pair Mismatch MeSH
• Nucleic Acid Denaturation MeSH
• Species Specificity MeSH
• Escherichia coli chemistry   MeSH
• Magnesium chemistry   MeSH
• Nucleic Acid Conformation MeSH
• Macromolecular Substances MeSH
• Models, Molecular * MeSH
• Base Pairing * MeSH
• Computer Simulation MeSH
• Motion MeSH
• RNA, Ribosomal, 5S chemistry   MeSH
• RNA, Plant chemistry   MeSH
• Solvents chemistry   MeSH
• Sodium chemistry   MeSH
• Spinacia oleracea chemistry   MeSH
• Binding Sites MeSH
• Water chemistry   MeSH
• Publication type
• Journal Article MeSH
• Evaluation Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH
• Comparative Study MeSH
• Validation Study MeSH
• Names of Substances
• RNA, Bacterial MeSH
• Magnesium MeSH
• Macromolecular Substances MeSH
• RNA, Ribosomal, 5S MeSH
• RNA, Plant MeSH
• Solvents MeSH
• Sodium MeSH
• Water MeSH