Environmental effects on the enhancement in natural and damaged DNA nucleobase acidity because of discrete hydrogen-bonding interactions

The present study uses density functional theory to carefully consider the effects of the environment on the enhancement in (natural and damaged) DNA nucleobase acidities because of multiple hydrogen-bonding interactions. Although interactions with one small molecule can increase the acidity of the nucleobases by up to 60 kJ mol-1 in the gas phase, the maximum increase in enzymatic-like environments is expected to be approximately 40 kJ mol-1, which reduces to approximately 30 kJ mol-1 in water. Furthermore, the calculated (simultaneous) effects of two, three, or four molecules are increasingly less than the sum of the individual (additive) effects with an increase in the number and acidity of the small molecules bound or the dielectric constant of the solvent. Regardless of these trends, our calculations reveal that additional hydrogen-bonding interactions will have a significant effect on nucleobase acidity in a variety of environments, where the exact magnitude of the effect depends on the properties of the small molecule bound, the nucleobase binding site, and the solvent. The maximum increase in nucleobase acidity because of interactions with up to four small molecules is approximately 80 kJ mol-1 in enzymatic-like environments (or 65 kJ mol-1 in water). These results suggest that hydrogen-bonding interactions likely play an important role in many biological processes by changing the physical and chemical properties of the nucleobases.     

Utilization of a combination of weak hydrogen-bonding interactions and phase segregation to yield highly thermosensitive supramolecular polymers

Supramolecular polymerization, i.e., the self-assembly of polymer-like materials through the utilization of the noncovalent bond, is a developing area of research. In this paper, we report the synthesis and investigation of nucleobase-terminated (N6-anisoyl-adenine and N4-(4-tert-butylbenzoyl)cytosine) low molecular weight poly(THF) macromonomers (<2000 g mol(-1)). Even though the degree of interaction between the nucleobase derivatives is very low (<5 M(-1)) these macromonomers self-assemble in the solid state to yield materials with film and fiber-forming capability. While the mechanical properties of films of both materials show extreme temperature sensitivity, resulting in the formation of very low viscosity melts, they do behave differently, which is attributed to the nature of the self-assembly controlled by the nucleobase. A combination of FT-IR, WAXD, and rheological experiments was carried out to further investigate the nature of the self-assembly in these systems. The studies demonstrate that a combination of phase segregation between the hard nucleobase chain ends and the soft poly(THF) core combined with aromatic amide hydrogen bonding is utilized to yield the highly thermosensitive supramolecular polymeric materials. In addition, analysis of the data suggests that the rheological properties of these supramolecular materials is controlled by the disengagement rate of the nucleobase chain ends from the "hard" phase, which, if shown to be general, provides a design criteria in the development of more thermally responsive materials.     

Effects on the aromatic character of DNA/RNA nucleobases due to its adsorption onto graphene

In the last years, experimental/theoretical studies have shown that graphene has a strong affinity toward nucleobases, serving as a promising nanomaterial for self‐assembly, sensing, and/or sequencing of DNA/RNA constituents. Then, a complete picture of the properties of the nucleobase–graphene systems is required for its use in technological applications. This work describes a detailed quantum chemical analysis of the aromaticity of adsorbed nucleobases on graphene, comparing between aromaticity indexes based on magnetic, geometry, electron density, and electron delocalization properties of graphene–nucleobase systems. Contrary to the stated by magnetic‐based aromaticity criteria (such as nucleus‐independent chemical shifts), it is proved that the aromatic character of nucleobases is not increased/decreased upon binding on graphene. Therefore, magnetic aromaticity criteria are not recommended to analyze aromaticity in related systems, unless a fragmented scheme be adopted. Finally, these results are expected to expand the knowledge about the understanding of biomolecules‐graphene interactions.     

Recent Advances and Future Prospects on Adaptive Biomaterials for Antimicrobial Applications

Bacterial infection is becoming the biggest threat to human health. The scenario is partly due to the ineffectiveness of the conventional antibiotic treatments against the emergence of multidrug‐resistant bacteria and partly due to the bacteria living in biofilms or cells. Adaptive biomaterials can change their physicochemical properties in the microenvironment of bacterial infection, thereby facilitating either their interactions with bacteria or drug release. The trends in treating bacterial infections using adaptive biomaterials‐based systems are flourishing and generate innumerous possibility to design novel antimicrobial therapeutics. This feature article aims to summarize the recent developments in the formulations, mechanisms, and advances of adaptive materials in bacterial infection diagnosis, contact killing of bacteria, and antimicrobial drug delivery. Also, the challenges and limitations of current antimicrobial treatments based on adaptive materials and their clinical and industrial future prospects are discussed.     

Noncovalent water-based materials: robust yet adaptive

The adaptive properties of noncovalent materials allow easy processing, facile recycling, self-healing, and stimuli responsiveness. However, the poor robustness of noncovalent systems has hampered their use in real-life applications. In this Concept Article we discuss the possibility of creating robust noncovalent arrays by utilizing strong hydrophobic interactions. We describe examples from our work on aqueous assemblies based on aromatic amphiphiles with extended hydrophobic cores. These arrays exhibit fascinating properties, including robustness, multiple stimuli-responsiveness, and pathway-dependent self-assembly. We have shown that this can lead to functional materials (filtration membranes) rivaling covalent systems. We anticipate that water-based noncovalent materials have the potential to replace or complement conventional polymer materials in various fields, and to promote novel applications that require the combination of robustness and adaptivity.     

H-bonding-directed self-assembly of synthetic copolymers containing nucleobases: organization and colloidal fusion in a noncompetitive solvent

The self-organization of random copolymers composed of a nucleobase monomer (either 1-(4-vinylbenzyl)thymine or 9-(4-vinylbenzyl)adenine) and dodecyl methacrylate (DMA) was studied in dilute chloroform solutions. The balance between the molar fractions of the nucleobase monomer (leading to intermolecular H-bonding) and DMA (soluble moiety in chloroform) in the polymer chains was found to be the parameter that principally influences the self-organization. DMA-rich copolymers are molecularly soluble in chloroform, whereas nucleobase-rich copolymers are insoluble in this solvent. Copolymers possessing an equimolar comonomer composition self-assemble into micrometer-sized particles physically cross-linked by intermolecular H-bonds (either thymine-thymine or adenine-adenine interactions, depending on the studied copolymer). Nevertheless, when mixed together, thymine- and adenine-based colloids fuse into thermodynamically stable microspheres cross linked by adenine-thymine interactions.     

Self-assembled microspheres from f-block elements and nucleoamphiphiles

Hollow microspheres featuring a hybrid lipid-cation multilamellar shell are prepared by hydration of a nucleoside based amphiphile with an aqueous solution containing either actinide or lanthanide salts. The physico-chemical data collected clearly indicate that the formation of these microspheres is a consequence of the following concomitant stabilizing factors: (i) hydrophobic interactions, (ii) nucleobase dimer formation and (iii) phosphate/f-block element salt binding.     

Computational comparison of the stacking interactions between the aromatic amino acids and the natural or (cationic) methylated nucleobases

The strongest gas-phase MP2/6-31G*(0.25) stacking energies between the aromatic amino acids and the natural or methylated nucleobases were considered. The potential energy surfaces of dimers were searched as a function of the vertical separation, angle of rotation and horizontal displacement between monomers stacked according to their centers of mass. Our calculations reveal that the stacking interactions of adducts for a given nucleobase are dependent on the methylation site (by up to 20 kJ mol(-1)), where the relative magnitudes of the interactions are determined by the dipole moments of the adducts and the proton affinities of nucleobase methylation sites. Nevertheless, the differences in the (gas-phase) stacking of methylated adducts are small compared with the differences between the stacking of the corresponding natural and methylated nucleobases. Indeed, methylation increases the stacking energy by up to 40 kJ mol(-1) (or 135%). Although immersing the dimers in different solvents decreases the gas-phase stacking energies with an increase in the polarity of the environment, base methylation still has a significant effect on the nucleobase stacking ability in solvents with large dipole moments, and, perhaps more importantly, environments that mimic enzyme active sites. Our results shed light on the workings of DNA repairs enzymes that selectively remove a wide variety of alkylated nucleobases over the natural bases.     

Effects of nucleobase metalation on frontier molecular orbitals: potential implications for pi-stacking interactions with tryptophan

Biochemical recognition processes mediated through pi-stacking interactions are a potential target for rational drug synthesis. A combination of electrostatic, hydrophobic, solvation, charge-transfer, induction, and dispersion interactions has been used to account for the three-dimensional arrangements observed in such motifs. A principal example involves the interaction of purine and pyrimidine rings of nucleic acids with aromatic amino-acid residues such as tryptophan, phenylalanine, and tyrosine. Protonation, alkylation, or coordination of a metal ion such as Pd(II) or Pt(II) to a nucleobase strengthens this interaction by lowering the energy of the lowest unoccupied molecular orbital (LUMO) of the modified nucleobase and improving overlap with the highest occupied molecular orbital (HOMO) in N-acetyl tryptophan. The relative energy difference between the frontier orbitals of isolated molecules, obtained using Density Functional Theory (DFT), is explored as a predictive tool for the strength of the pi-stacking interaction of the nucleobase/tryptophan pair. From the optimized structures of these species, evaluation of the donor-acceptor HOMO-LUMO gap (Deltaepsilon d-->a) suggests that this parameter is a promising predictor of pi-stacking strength for the donor-acceptor pairs presented in this study. The analysis correlates well with experimental association constants, measured by fluorescence spectroscopy, of metallated and alkylated nucleobases with tryptophan in comparison to free nucleobases.     

Molecular recognition via base-pairing

Hydrogen-bonding interactions in DNA/RNA systems are a defining feature of double helical systems. They also play a critical role in stabilizing other higher-order structures, such as hairpin loops, and thus in the broadest sense can be considered as key requisites to the successful translation and replication of genetic information. This importance, coupled with the aesthetic appeal of nucleic acid base (nucleobase) hydrogen-bond interactions, has inspired the use of such motifs to stabilize a range of synthetic structures. This, in turn, has led to the formation of a number of novel ensembles. This tutorial review will discuss these structures, both from a synthetic perspective and in terms of their potential application in areas that include, but are not limited to, self-assembled macrocyclic and high-order ensemble synthesis, supramolecular polymer preparation, molecular cage construction, and energy and electron transfer modeling.     

An experimental and theoretical study of the gas-phase decomposition of monoprotonated peptide nucleic acids

Peptide nucleic acids (PNAs) are DNA/RNA mimics which have recently generated considerable interest due to their potential use as antisense and antigene therapeutics and as diagnostic and molecular biology tools. These synthetic biomolecules were designed with improved properties over corresponding oligonucleotides such as greater binding affinity to complementary nucleic acids, enhanced cellular uptake, and greater stability in biological systems. Because of the stability and unique structure of PNAs, traditional sequence confirmation methods are not effective. Alternatively, electrospray ionization coupled with Fourier transform ion cyclotron resonance mass spectrometry shows great potential as a tool for the characterization and structural elucidation of these oligonucleotide analogs. Extensive gas-phase fragmentation studies of a mixed nucleobase 4-mer (AACT) and a mixed nucleobase 4-mer with an acetylated N-terminus (N-acetylated AACT) have been performed. Gas-phase collision-induced dissociation of PNAs resulted in water loss, cleavage of the methylene carbonyl linker containing a nucleobase, cleavage of the peptide bond, and the loss of nucleobases. These studies show that the fragmentation behavior of PNAs resembles that of both peptides and oligonucleotides. Molecular mechanics (MM+), semiempirical (AM1), and ab initio (STO-3G) calculations were used to investigate the site of protonation and determine potential low energy conformations. Computational methods were also employed to study prospective intramolecular interactions and provide insight into potential fragmentation mechanisms.     

Liquid‐Crystalline Supramolecular Polymers Formed through Complementary Nucleobase‐Pair Interactions

We report how the placement of nucleobase units, thymine, or N ⁶‐(4‐methoxybenzoyl)adenine, onto the ends of a mesogenic core, bis‐4‐alkoxy‐substituted bis(phenylethynyl)benzene, affects the properties of these materials. We show that addition of these bulky polar groups significantly reduces the range of liquid‐crystalline behavior of these compounds. However, mixing two complementary nucleobase‐containing AA‐ and BB‐type monomer units together does result in the formation of stable, thermotropic liquid‐crystalline (LC) phases. Hydrogen bonding is shown to play an important role in the formation of these LC phases, consistent with the formation of oligomeric or polymeric hydrogen‐bonded aggregates. X‐ray analyses of these mixed materials are consistent with the formation of smectic C phases.     

A kinetic and thermodynamic study of the glycosidic bond cleavage in deoxyuridine

Density functional theory was used to study the thermodynamics and kinetics for the glycosidic bond cleavage in deoxyuridine. Two reaction pathways were characterized for the unimolecular decomposition in vacuo. However, these processes are associated with large reaction barriers and highly endothermic reaction energies, which is in agreement with experiments that suggest a (water) nucleophile is required for the nonenzymatic glycosidic bond cleavage. Two (S(N)1 and S(N)2) reaction pathways were characterized for direct hydrolysis of the glycosidic bond by a single water molecule; however, both pathways also involve very large barriers. Activation of the water nucleophile via partial proton abstraction steadily decreases the barrier and leads to a more exothermic reaction energy as the proton affinity of the molecule interacting with water increases. Indeed, our data suggests that the barrier heights and reaction energies range from that for hydrolysis by water to that for hydrolysis by the hydroxyl anion, which represents the extreme of (full) water activation (deprotonation). Hydrogen bonds between small molecules (hydrogen fluoride, water, or ammonia) and the nucleobase were found to further decrease the barrier and overall reaction energy but not to the extent that the same hydrogen-bonding interactions increase the acidity of the nucleobase. Our results suggest that the nature of the nucleophile plays a more important role in reducing the barrier to glycosidic bond cleavage than the nature of the small molecule bound, and models with more than one hydrogen fluoride molecule interacting with the nucleobase provide further support for this conclusion. Our results lead to a greater fundamental understanding of the effects of the nucleophile, activation of the nucleophile, and interactions with the nucleobase for this important biological reaction.     

Double Functionalization of Carbon Nanotubes with Purine and Pyrimidine Derivatives

Herein, we have developed a synthetic strategy for the covalent double functionalization of single‐walled carbon nanotubes (SWCNTs) with a combination of purine–pyrimidine and purine–purine nucleobase systems. The nucleobases were introduced on the sidewall of oxidized SWCNTs through 1,3‐dipolar cycloaddition and by amidation of the carboxylic acids located at the tips and defect sites of the nanotubes. The new nanohybrids were characterized by transmission electron microscopy, thermogravimetric analysis, FTIR and Raman spectroscopy, magic‐angle spinning NMR spectroscopy, and Kaiser test. The nucleobase/SWCNT conjugates can be envisaged for the modulation of the interactions with nucleic acids by means of base pairing, thereby opening new possibilities in the development of DNA/CNT nanobioconjugates.     

An application of the van der Waals density functional: Hydrogen bonding and stacking interactions between nucleobases

We apply the van der Waals density functional (vdW-DF) to study hydrogen bonding and stacking interactions between nucleobases. The excellent agreement of our results with high level quantum chemical calculations highlights the value of the vdW-DF for first-principles investigations of biologically important molecules. Our results suggest that, in the case of hydrogen-bonded nucleobase pairs, dispersion interactions reduce the cost of propeller twists while having a negligible effect on buckling. Furthermore, the efficient scaling of DFT methods allowed for the easy optimization of separation distance between nucleobase stacks, indicating enhancements in the interaction energy of up to 3 kcalmol over previous fixed distance calculations. We anticipate that these results are significant for extending the vdW-DF method to model larger vdW complexes and biological molecules.     

Some halogenated anticancer agents,role of halide (-X) and their interaction mechanism with AT/GC base pairs: A computational study

Recently, a new class of halogen-based active anticancer agents have widely been developed which shows effective binding with AT/GC base pairs of DNA nucleobases. Usually intercalation, groove binding and covalent binding mechanisms are the most common drug-DNA binding pathways; but, the groove binding mechanism plays a crucial role in the stability of such drug-DNA complexes. As anticancer agent-DNA nucleobase interactions are very difficult to investigate by using common experimental techniques; therefore, theoretical methods may be quite helpful to analyze the proper mode of interaction for such drug-DNA systems. Past literature reveals that, quantum mechanical (QM) density functional theory (DFT) method is one of the best known tool for analyzing the different binding modes of halogenated anticancer agents with DNA nucleobases. Moreover, the halogen-bonding interaction in any biological system is fundamentally understood by investigating the mechanism of donor-acceptor complex formation between donor halogens and acceptor atoms within a receptor; such study is very competent for exploring the favoured anticancer agent-DNA interaction. In this current work, our main objective is to explore the effect of some intercalating and groove binding halogen-based anticancer agents with DNA nucleobase using computational method.     

A comparative DFT study of some N-based aromatic ligand metal complexes as anticancer agents and analysis of their mode of interaction with DNA base pair

Metal complexed anticancer agents interact with DNA nucleobase pairs (AT and GC) through different types of binding mode such as intercalation, groove binding, covalent binding, etc. Minor and major groove binding mechanism of DNA base pair is the key factor for all kinds of anticancer agent; as metal complexes have a great affinity to bind with DNA nucleobase either through minor or major groove. Ligands in metal complexes also play a vital role during the interaction with DNA base pairs; these ligands directly interact with DNA through different interacting modes. Generally, anticancer agents with less sterically hindered N-based aromatic and planar ligands are the key component for DNA binding; as the structure of such ligands are quite compatible for following intercalation and groove binding mechanism. Since, the experimental investigation for drug-DNA nucleobase complexes are extremely complicated, therefore; quantum mechanical calculations might be very helpful for computing the actual interactions in drug-DNA complexes. Quantum mechanical approaches such as density functional theory (DFT) might be a very important and useful tool to investigate the actual mode of interaction of metal complexed antitumor agents with DNA nucleobase. Herein, we have taken some metal complexes with N-based aromatic ligands as antitumor agents to investigate the proper mode of interaction between drug-DNA complexes.     

Spatial,Hysteretic, and Adaptive Host–Guest Chemistry in a Metal–Organic Framework with Open Watson–Crick Sites

Biological and artificial molecules and assemblies capable of supramolecular recognition, especially those with nucleobase pairing, usually rely on autonomous or collective binding to function. Advanced site‐specific recognition takes advantage of cooperative spatial effects, as in local folding in protein–DNA binding. Herein, we report a new nucleobase‐tagged metal–organic framework (MOF), namely ZnBTCA (BTC=benzene‐1,3,5‐tricarboxyl, A=adenine), in which the exposed Watson–Crick faces of adenine residues are immobilized periodically on the interior crystalline surface. Systematic control experiments demonstrated the cooperation of the open Watson–Crick sites and spatial effects within the nanopores, and thermodynamic and kinetic studies revealed a hysteretic host–guest interaction attributed to mild chemisorption. We further exploited this behavior for adenine–thymine binding within the constrained pores, and a globally adaptive response of the MOF host was observed.     

Triostin A Derived Cyclopeptide as Architectural Template for the Alignment of Four Recognition Units

The DNA bisintercalator triostin A is structurally based on a disulfide-bridged depsipeptide scaffold that provides preorganization of two quinoxaline units in 10.5 Å distance. Triostin A analogues are synthesized with nucleobase recognition units replacing the quinoxalines and containing two additional recognition units in between. Thus, four nucleobase recognition units are organized on a rigid template, well suited for DNA double strand interactions. The new tetra-nucleobase binders are synthesized as aza-TANDEM derivatives lacking the N-methylation of triostin A and based on a cyclopeptide backbone. Synthesis of two tetra-nucleobase aza-TANDEM derivatives is established, DNA interaction analyzed by microscale thermophoresis, cytotoxic activity studied and a nucleobase sequence dependent self-aggregation investigated by mass spectrometry.