Nucleobase Interactions Research Articles

Theophylline alkaloid as glue of paddle-wheel copper(II)-adenine entities to afford a rhomboid chain

This work is aimed at the analysis of the interactions that drive the assembling of coordination metal-organic polymers based on biological molecules. Single-crystal X-ray diffraction data show that the compound 1D-{[Cu2(μ-ade)4(H2O)2]·2[Cu(theoph)2]·∼10H2O}n (1) contains neutral rhomboid shaped chains sustained by the tridentate μ3-κN3:κN7:κN9 coordination mode of the adenine nucleobase. These chains are formed by dimeric copper/adeninato (ade) cores doubly bridged by monomeric copper/theophyllinato (theoph) entities with the alkaloid acting as peripheral ligand. The lack of direct intermolecular nucleobase···nucleobase interactions, due to their disruption by the crystallization water molecules, does not provide a highly porous material, but the irregular shape of the polymeric chain hinders their packing and allows the presence of a moderate amount of voids (16% of the unit cell volume) in good accordance with its adsorption capacity of 0.38 mmol CO2/g at 273 K. Thermogravimetric and variable temperature X-ray diffraction analyses show that the compound retains its structure up to 110 °C whereas above this temperature the release of the coordination water molecules produces a significant loss of crystallinity. Magnetic measurements indicate an overall antiferromagnetic behavior with a J value of −267 cm−1 within the dimeric entity.

Density functional study on the binding properties of nucleobases to stanane nanosheet

We report the interaction of stanane nanosheet (Sn-NS) with deoxy ribo nucleic acids (DNA)/ribo nucleic acids (RNA) utilizing density functional theory (DFT) technique. The calculated formation energy led us to conclude that Sn-NS exhibits a stable geometric structure. The energy band structure and density of states (DOS) spectrum provide the electronic characteristics of Sn-NS, and the band gap is found to be 1.73 eV, which exhibit semiconducting property. Our results confirmed the adsorption of nucleobases with stanane nanosheet, which follows the sequence C > U > A > T > G. The interaction property of nucleobases on Sn-NS material is authenticated with the Bader charge transfer, energy gap, adsorption energy and average energy gap changes. Moreover, the interaction of nucleobases on Sn-NS is also explored using the change in the DOS-spectrum, electron density diagrams and energy band structure. The findings of the current work infer that the DNA sequencing can be carried out using stanane nanosheet.

Computational study on the interaction of nucleobases with boron-rich boron nitride nanotubes

Computational study on the interaction of nucleobases with boron-rich boron nitride nanotubes

Quantifying Interactions of Nucleobase Atoms with Model Compounds for the Peptide Backbone and Glutamine and Asparagine Side Chains in Water.

Alkylureas display hydrocarbon and amide groups, the primary functional groups of proteins. To obtain the thermodynamic information that is needed to analyze interactions of amides and proteins with nucleobases and nucleic acids, we quantify preferential interactions of alkylureas with nucleobases differing in the amount and composition of water-accessible surface area (ASA) by solubility assays. Using an established additive ASA-based analysis, we interpret these thermodynamic results to determine interactions of each alkylurea with five types of nucleobase unified atoms (carbonyl sp2O, amino sp3N, ring sp2N, methyl sp3C, and ring sp2C). All alkylureas interact favorably with nucleobase sp2C and sp3C atoms; these interactions become more favorable with an increasing level of alkylation of urea. Interactions with nucleobase sp2O are most favorable for urea, less favorable for methylurea and ethylurea, and unfavorable for dialkylated ureas. Contributions to overall alkylurea-nucleobase interactions from interactions with each nucleobase atom type are proportional to the ASA of that atom type with proportionality constant (interaction strength) α, as observed previously for urea. Trends in α-values for interactions of alkylureas with nucleobase atom types parallel those for corresponding amide compound atom types, offset because nucleobase α-values are more favorable. Comparisons between ethylated and methylated ureas show interactions of amide compound sp3C with nucleobase sp2C, sp3C, sp2N, and sp3N atoms are favorable while amide sp3C-nucleobase sp2O interactions are unfavorable. Strongly favorable interactions of urea with nucleobase sp2O but weakly favorable interactions with nucleobase sp3N indicate that amide sp2N-nucleobase sp2O and nucleobase sp3N-amide sp2O hydrogen bonding (NH···O═C) interactions are favorable while amide sp2N-nucleobase sp3N interactions are unfavorable. These favorable amide-nucleobase hydrogen bonding interactions are prevalent in specific protein-nucleotide complexes.

Nucleobase-Containing Polymers: Structure, Synthesis, and Applications.

Nucleobase interactions play a fundamental role in biological functions, including transcription and translation. Natural nucleic acids like DNA are also widely implemented in material realm such as DNA guided self-assembly of nanomaterials. Inspired by that, polymer chemists have contributed phenomenal endeavors to mimic both the structures and functions of natural nucleic acids in synthetic polymers. Similar sequence-dependent responses were observed and employed in the self-assembly of these nucleobase-containing polymers. Here, the structures, synthetic approaches, and applications of nucleobase-containing polymers are highlighted and a brief look is taken at the future development of these polymers.

Reversibly Manipulating the Surface Chemistry of Polymeric Nanostructures via a "Grafting To" Approach Mediated by Nucleobase Interactions.

“Grafting to” polymeric nanostructures or surfaces is a simple and versatile approach to achieve functionalization. Herein, we describe the formation of mixed polymer-grafted nanoparticles through a supramolecular “grafting to” method that exploits multiple hydrogen-bonding interactions between the thymine (T)-containing cores of preformed micelles and the complementary nucleobase adenine (A) of added diblock copolymers. To demonstrate this new “grafting to” approach, mixed-corona polymeric nanoparticles with different sizes were prepared by the addition of a series of complementary diblock copolymers containing thermoresponsive poly(N-isopropylacrylamide) (PNIPAM) to a preformed micelle with a different coronal forming block, poly(4-acryloylmorpholine) (PNAM). PNIPAM chains were distributed throughout the corona and facilitated a fast and fully reversible size change of the resulting mixed-corona micelles upon heating. Through the introduction of an environmentally sensitive fluorophore, the reversible changes in nanoparticle size and coronal composition could be easily probed. Furthermore, preparation of mixed-corona micelles also enabled ligands, such as d-mannose, to be concealed and displayed on the micelle surface. This supramolecular “grafting to” approach provides a straightforward route to fabricate highly functionalized mixed polymeric nanostructures or surfaces with potential applications in targeted diagnosis or therapy and responsive surfaces.

Pyridine: a Denaturant or Stabilizer of Spherical Nucleic Acids?

The spotlighted dual functions of pyridine as a denaturant and as a stabilizer for duplex DNA are thoroughly investigated using spherical nucleic acids (SNAs). At neutral pH, pyridine destabilizes the duplex interconnects of assembled SNAs, resulting in a gradual decrease in their melting temperature (Tm) as a function of the pyridine concentration. This result is in good agreement with the conventional role of pyridine as a powerful denaturant for free duplex DNA. On the contrary, the addition of pyridine dramatically increases the Tm of hybridized SNAs under acidic conditions, which could be a striking result of pyridine's stabilizing effect for DNA duplex as previously suggested on the basis of the pyridine-nucleobase interactions. After comprehensive and quantitative investigation based on the analysis of the sharp melting transitions of SNAs, however, we report that, in fact, the pH increase induced by pyridine is also an essential parameter accounting for pyridine's DNA-stabilizing effects under acidic conditions. Importantly, we prove that pyridine, particularly at a low concentration, does not increase the Tm of hybridized SNAs even under acidic conditions, if the pH increase by pyridine is corrected to maintain the same initial pH.

Interaction of nucleobases with silicene nanoribbon: A density functional approach

Silicene, a hexagonal buckled 2D allotrope of silicon, shows potential for numerous new applications, and may allow for easier integration with existing silicon-based microelectronics than graphene. The possibility of the application of silicene as a biosensor is discussed. The interaction between a hydrogen-passivated zigzag silicene nanoribbon (ZSiNR) and the nucleic acid bases, adenine (A), guanine (G), cytosine (C) and thymine (T), is investigated by density functional theory. The binding energy of the nucleobase-stacked nanoribbons shows the following order: G>C>A>T.

Reactivity of nitrogen atoms in adenine and (Ade)2Cu complexes towards ribose and 2-furanmethanol: Formation of adenosine and kinetin

To explore the interaction of nucleosides and nucleobases in the context of the Maillard reaction and to identify the selectivity of purine nitrogen atoms towards various electrophiles, model systems composed of adenine or adenosine, glycine, ribose and/or 2-furanmethanol (with and without copper) were studied in aqueous solutions heated at 110°C for 2h and subsequently analyzed by ESI/qTOF/MS/MS in addition to isotope labelling techniques. The results indicated that ribose selectively formed mono-ribosylated N6 adenine, but in the presence of (Ade)2Cu complex the reaction mixture generated mono-, di- and tri-substituted sugar complexes and their hydrolysis products of mono-ribosylated N6 and N9 adenine adducts and di-ribosylated N6,9 adenine. Furthermore, the reaction of 2-furanmethanol with adenine in the presence of ribose generated kinetin and its isomer, while its reaction with adenosine generated kinetin riboside, as confirmed by comparing the MS/MS profiles of these adducts to those of commercial standards.

The Renaissance of Metal-Pyrimidine Nucleobase Coordination Chemistry.

The significance of metal ions for the function and properties of DNA and RNA, long seen primarily under biological aspects and medicinal uses, has recently gained a renewed momentum. This is a consequence of the advent of novel applications in the fields of materials science, biotechnology, and analytical sensor chemistry that relate to the designed incorporation of transition metal ions into nucleic acid base pairs. Ag(+) and Hg(2+) ions, binding to pyrimidine (pym) nucleobases, represent major players in this development. Interestingly, these metal ions were the ones that some 60 years ago started the field! At the same time, the mentioned metal ions had demonstrated a "special relationship" with the pym nucleobases cytosine, thymine, and uracil! Parallel work conducted with oligonucleotides and model nucleobases fostered numerous significant details of these interactions, in particular when X-ray crystallography was involved, correcting earlier views occasionally. Our own activities during the past three to four decades have focused on, among others, the coordination chemistry of transition and main-group metal ions with pym model nucleobases, with an emphasis on Pt(II) and Pd(II). It has always been our goal to deduce, if possible, the potential relevance of our findings for biological processes. It is interesting to put our data, in particular for trans-a2Pt(II) (a = NH3 or amine), into perspective with those of other metal ions, notably Ag(+) and Hg(2+). Irrespective of major differences in kinetics and lability/inertness between d(8) and d(10) metal ions, there is also a lot of similarity in structural aspects as a result of the preferred linear coordination geometry of these species. Moreover, the apparent clustering of metal ions to the pym nucleobases, which is presumably essential for the formation of nanoclusters on oligonucleotide scaffolds, is impressively reflected in model systems, as are reasons for inter-nucleobase cross-links containing more than a single metal ion. The present understanding of these interrelationships is a consequence of intensive research carried out during the last 60 years by numerous laboratories. For space restrictions in this Account, it was impossible to adequately highlight the valuable contributions of all of the researchers in the field of metal-pym nucleobase interactions. Explicitly this refers to colleagues not cited in the references, e.g., R. Stuart Tobias, Robert Bau, R. Bruce Martin, Colin J. L. Lock, Katsuyuki Aoki, Helmut Sigel, and Michael J. Clarke, among others.

Surface-Enhanced Hyper-Raman Spectra of Adenine, Guanine, Cytosine, Thymine, and Uracil.

Using picosecond excitation at 1064 nm, surface-enhanced hyper-Raman scattering (SEHRS) spectra of the nucleobases adenine, guanine, cytosine, thymine, and uracil with two different types of silver nanoparticles were obtained. Comparing the SEHRS spectra with SERS data from the identical samples excited at 532 nm and with known infrared spectra, the major bands in the spectra are assigned. Due to the different selection rules for the one- and two-photon excited Raman scattering, we observe strong variation in relative signal strengths of many molecular vibrations obtained in SEHRS and SERS spectra. The two-photon excited spectra of the nucleobases are found to be very sensitive with respect to molecule–nanoparticle interactions. Using both the SEHRS and SERS data, a comprehensive vibrational characterization of the interaction of nucleobases with silver nanostructures can be achieved.

Interaction of nucleobases with silicon doped and defective silicon doped graphene and optical properties.

The interaction of nucleobases (NBs) with the surface of silicon doped graphene (SiGr) and defective silicon doped graphene (dSiGr) has been studied using electronic structure methods. A systematic comparison of the calculated interaction energies (adsorption strength) of NBs with the surface of SiGr and dSiGr with those of pristine graphene (Gr) has also been made. The doping of graphene with silicon increases the adsorption strength of NBs. The introduction of defects in SiGr further enhances the strength of interaction with NBs. The appreciable stability of complexes (SiGr-NBs and dSiGr-NBs) arises due to the partial electrostatic and covalent (Si···O(N)) interaction in addition to π-π stacking. The interaction energy increases with the size of graphene models. The strong interaction between dSiGr-NBs and concomitant charge transfer causes significant changes in the electronic structure of dSiGr in contrast to Gr and SiGr. Further, the calculated optical properties of all the model systems using time dependent density functional theory (TD-DFT) reveal that absorption spectra of SiGr and dSiGr undergo appreciable changes after adsorption of NBs. Thus, the significant variations in the HOMO-LUMO gap and absorption spectra of dSiGr after interaction with the NBs can be exploited for possible applications in the sensing of DNA nucleobases.

Response of chitosan–nucleobase interaction toward external perturbations: A computational study

The present study delves into the impact of external perturbation in the form of solvent and external electric field on the interaction energy and reactivity descriptors of chitosan–nucleobase adducts. Interaction energy is found to be significantly influenced by both the factors. Positive interaction energy indicating repulsive interaction between chitosan and nucleobases is observed at high field strengths applied along particular directions. Stability of adducts are found insensitive toward the change in polarity of the solvent. Modulating external perturbation in the form of electric field and polarity of solvent media might be envisaged as a tool for tuning gene delivery by chitosan.

Cross-species conservation of complementary amino acid-ribonucleobase interactions and their potential for ribosome-free encoding.

The role of amino acid-RNA nucleobase interactions in the evolution of RNA translation and protein-mRNA autoregulation remains an open area of research. We describe the inference of pairwise amino acid-RNA nucleobase interaction preferences using structural data from known RNA-protein complexes. We observed significant matching between an amino acid’s nucleobase affinity and corresponding codon content in both the standard genetic code and mitochondrial variants. Furthermore, we showed that knowledge of nucleobase preferences allows statistically significant prediction of protein primary sequence from mRNA using purely physiochemical information. Interestingly, ribosomal primary sequences were more accurately predicted than non-ribosomal sequences, suggesting a potential role for direct amino acid-nucleobase interactions in the genesis of amino acid-based ribosomal components. Finally, we observed matching between amino acid-nucleobase affinities and corresponding mRNA sequences in 35 evolutionarily diverse proteomes. We believe these results have important implications for the study of the evolutionary origins of the genetic code and protein-mRNA cross-regulation.

Synthesis and X-ray crystal structure of the dirhenium complex Re2(i-C3H7COO)4Cl2 and its interactions with the DNA purine nucleobases

The dirhenium complex Re2(i-C3H7COO)4Cl2 was synthesized and characterized by X-ray crystallography, 1H NMR and electronic spectroscopies, and electrospray ionization-mass spectrometry. The reactions of Re2(i-C3H7COO)4Cl2 with the substituted DNA purine nucleobases guanine (9-methylguanine and 9-ethylguanine) and adenine (9-methyladenine and 9-ethyladenine) were investigated by proton nuclear magnetic resonance and electronic spectroscopies as well as electrospray ionization-mass spectrometry. The data corroborate binding of two 9-methylguanine (or 9-ethylguanine) and 9-methyladenine (or 9-ethyladenine) bases per dirhenium unit in a bidentate fashion, in equatorial positions, via sites N7/O6 and N1/N6, respectively, with concomitant substitution of two carboxylate groups to form a single isomer of cis-Re2(i-C3H7COO)2(nucleobase)2Cl2. The binding of the bases to the dirhenium core disrupts important nucleobase interactions and may have important biological implications with respect to the anticancer activity of dirhenium complexes.

Gamma Peptide Nucleic Acids: As Orthogonal Nucleic Acid Recognition Codes for Organizing Molecular Self-Assembly.

Nucleic acids are an attractive platform for organizing molecular self-assembly because of their specific nucleobase interactions and defined length scale. Routinely employed in the organization and assembly of materials in vitro, however, they have rarely been exploited in vivo, due to the concerns for enzymatic degradation and cross-hybridization with the host's genetic materials. Herein we report the development of a tight-binding, orthogonal, synthetically versatile, and informationally interfaced nucleic acid platform for programming molecular interactions, with implications for in vivo molecular assembly and computing. The system consists of three molecular entities: the right-handed and left-handed conformers and a nonhelical domain. The first two are orthogonal to each other in recognition, while the third is capable of binding to both, providing a means for interfacing the two conformers as well as the natural nucleic acid biopolymers (i.e., DNA and RNA). The three molecular entities are prepared from the same monomeric chemical scaffold, with the exception of the stereochemistry or lack thereof at the γ-backbone that determines if the corresponding oligo adopts a right-handed or left-handed helix, or a nonhelical motif. These conformers hybridize to each other with exquisite affinity, sequence selectivity, and level of orthogonality. Recognition modules as short as five nucleotides in length are capable of organizing molecular assembly.

DNA nucleobase interaction with graphene like BC3 nano-sheet based on density functional theory calculations

We report the interaction of various nucleobases (guanine (G), adenine (A), thymine (T) and cytosine (C)) with a graphene-like BC3 nanosheet using dispersion corrected B3LYP level of theory. It was found that simultaneous contribution of dispersive forces and covalent bonds provides the stability of the bioconjugated complexes. Adenine has the maximum adsorption energy in both of gas and water phases; and the sequence of the adsorption strength without including the solvation effects decreases in the order A>T>C>G. The inclusion of solvation energy changes the order of binding preference to be A>C>T>G.

Measurements of single nucleotide electronic states as nanoelectronic fingerprints for identification of DNA nucleobases, their protonated and unprotonated states, isomers, and tautomers.

Several nanoelectronic techniques have been explored to distinguish the sequence of nucleic acids in DNA macromolecules. Identification of unique electronic signatures using nanopore conductance, tunneling spectroscopy, or other nanoelectronic techniques depends on electronic states of the DNA nucleotides. While several experimental and computational studies have focused on interaction of nucleobases with different substrates, the effect of nucleic acid biochemistry on its electronic properties has been largely unexplored. Here, we present correlated measurements of frontier molecular orbitals and higher-order electronic states for four DNA nucleobases (adenine, cytosine, thymine, and guanine), and first-principle quantum chemical density functional theoretical (DFT) computations. Using different pH conditions in our experiments, we show that small changes in the biochemical state of these nucleic acids strongly affect the intrinsic electronic structure, measured using scanning tunneling spectroscopy (STS). In our experimental measurements and computations, significant differences were observed between the position of frontier orbitals and higher-energy states between protonated and unprotonated nucleic acids, isomers, and different keto-enol tautomer's formed in these nucleotides, leading to their facile identification. Furthermore, we show unique "electronic fingerprints" for all nucleotides (A, G, T, C) using STS, with most distinct states identified at acidic pH. These results can have important implications for identification of nucleic acid sequences in DNA molecules using a high-throughput nanoelectronic identification technique.

Molecular Modeling and Simulations of DNA at Graphene-Water Interfaces towards Developing Biosensors and Drug Delivery Vehicles

The biocompatibility of Graphene oxide (GO) surfaces and their preferential affinity to single stranded DNA (ssDNA) over double stranded DNA (dsDNA) make GO-ssDNA complexes an attractive target for drug delivery applications. GO-ssDNA complexes also hold promise as biosensors: fluorescence can be achieved by desorption of fluorescently tagged ssDNA from GO surfaces by their complementary strands or DNA-binding proteins in solution. To tune nucleic acid sequences for targeting specific molecules, and to achieve high sensing abilities, it is important to quantify the interaction of individual nucleobases (A, T, G & C) and small oligonucleotides with GO or graphene surfaces, and understand the molecular mechanisms involved. Although experimental studies in the past (ITC, AFM) have focused on graphene-nucleobase interaction in water, and a few theoretical studies have focused on the same interaction in vacuum, a quantitative understanding of graphene-nucleic acid interaction still remains elusive. To this end, we performed molecular dynamics simulations, guided by dispersion-corrected density functional theory (DFT) and ITC experiments, to accurately quantify and understand the molecular mechanism of nucleobases and nucleosides binding to graphene surfaces in water. As part of this work, we modified the AMBER-99 all-atom molecular dynamics force-field parameters to accurately capture the van der Waals interaction between the atoms of the nucleobases and graphene. We rescaled the size of the graphene carbon and nucleobase atoms to match the graphene-nucleobase interaction energy profile in vacuum obtained using DFT calculations, and further rescaled the interaction energies to reproduce the binding free-energies in water obtained through ITC experiments. Our results provide a quantitative understanding of nucleobase-graphene interactions, and also build a platform to understand ssDNA binding to graphene surfaces, duplex formation at the graphene-water interface and their subsequent release to the bulk.

A Nucleobase-Centric Coarse-Grained Model for Structure Prediction of RNA Fragments

The structural characterization of RNA usually poses additional challenges when compared to other biomolecular systems. For example, there is a relatively scarce amount of structural data available, which demands the development of three-dimensional structure prediction tools. In addition, full-resolution simulations can be a hard task not only because of the complexity of the interactions involved, but also due to the limitations of the current force fields. At this point, coarse-grained simulations are a good candidate to fill the gaps in this growing research field. The use of these techniques has rapidly increased in the past decades in the study of biological systems on which the experiments require an additional interpretation or where an atomistic computational approach results difficult or unfeasible. Nevertheless, the development of coarse-grained models involves the understanding of the main structural features of the original system, which can represent a challenge by itself.In this work, we present a knowledge-base coarse-grained model for RNA structure prediction, representing each nucleotide by a single anisotropic particle. The mapping and the main interactions are designed to reproduce the geometrical distribution of the closest pairs of nucleotides, extracted from a set of ribosomal structures. The model is inspired in the ESCORE function [1], a knowledge-based scoring function that has been shown to perform better compared to fully atomistic techniques in identifying native-like structures from a set of decoys. Its minimalistic nature and successful application on a broad range of structures straightforwardly suggest a representation for a coarse-grained approach. We show the preliminary results of our simulations and discuss the role of pair interactions in the prediction of RNA structures.[1] S. Bottaro, F. Di Palma and G. Bussi, “The Role of Nucleobase Interactions in RNA Structure and Dynamics”, Nucleic Acids Res., accepted.