Synthesis of 1,4-Disubstituted Mono and Bis-triazolocarbo-acyclonucleoside Analogues of 9-(4-Hydroxybutyl)guanine by Cu(I)-Catalyzed Click Azide-Alkyne Cycloaddition

A series of novel mono-1,2,3-triazole and bis-1,2,3-triazole acyclonucleoside analogues of 9-(4-hydroxybutyl)guanine was prepared via copper(I)-catalyzed 1,3-dipolar cycloaddition of N-9 propargylpurine, N-1-propargylpyrimidines/as-triazine with the azido-pseudo-sugar 4-azidobutylacetate under solvent-free microwave conditions, followed by treatment with K2CO3/MeOH, or NH3/MeOH. All compounds studied in this work were screened for their antiviral activities [against human rhinovirus (HRV) and hepatitis C virus (HCV)] and antibacterial activities against a series of Gram positive and negative bacteria

Nitrogen doping of carbon nanoelectrodes for enhanced control of DNA translocation dynamics

Controlling the dynamics of DNA translocation is a central issue in the emerging nanopore-based DNA sequencing. To address the potential of heteroatom doping of carbon nanostructures to achieve this goal, herein we carry out atomistic molecular dynamics simulations for single-stranded DNAs translocating between two pristine or doped carbon nanotube (CNT) electrodes. Specifically, we consider the substitutional nitrogen doping of capped CNT (capCNT) electrodes and perform two types of molecular dynamics simulations for the entrapped and translocating single-stranded DNAs. We find that the substitutional nitrogen doping of capCNTs stabilizes the edge-on nucleobase configurations rather than the original face-on ones and slows down the DNA translocation speed by establishing hydrogen bonds between the N dopant atoms and nucleobases. Due to the enhanced interactions between DNAs and N-doped capCNTs, the duration time of nucleobases within the nanogap was extended by up to ~ 290 % and the fluctuation of the nucleobases was reduced by up to ~ 70 %. Given the possibility to be combined with extrinsic light or gate voltage modulation methods, the current work demonstrates that the substitutional nitrogen doping is a promising direction for the control of DNA translocation dynamics through a nanopore or nanogap based of carbon nanomaterials.Comment: 11 pages, 4 figure

Physisorption of Nucleobases on Graphene

We report the results of our first-principles investigation on the interaction of the nucleobases adenine (A), cytosine (C), guanine (G), thymine (T), and uracil (U) with graphene, carried out within the density functional theory framework, with additional calculations utilizing Hartree--Fock plus second-order Moeller-Plesset perturbation theory. The calculated binding energy of the nucleobases shows the following hierarchy: G > T ~ C ~ A > U, with the equilibrium configuration being very similar for all five of them. Our results clearly demonstrate that the nucleobases exhibit significantly different interaction strengths when physisorbed on graphene. The stabilizing factor in the interaction between the base molecule and graphene sheet is dominated by the molecular polarizability that allows a weakly attractive dispersion force to be induced between them. The present study represents a significant step towards a first-principles understanding of how the base sequence of DNA can affect its interaction with carbon nanotubes, as observed experimentally.Comment: 7 pages, 3 figure

Controlling platinum, ruthenium, and osmium reactivity for anticancer drug design

The main task of the medicinal chemist is to design molecules that interact specifically with derailed or degenerating processes in a diseased organism, translating the available knowledge of pathobiochemical and physiological data into chemically useful information and structures. Current knowledge of the biological and chemical processes underlying diseases is vast and rapidly expanding. In particular the unraveling of the genome in combination with, for instance, the rapid development of structural biology has led to an explosion in available information and identification of new targets for chemotherapy. The task of translating this wealth of data into active and selective new drugs is an enormous, but realistic, challenge. It requires knowledge from many different fields, including molecular biology, chemistry, pharmacology, physiology, and medicine and as such requires a truly interdisciplinary approach. Ultimately, the goal is to design molecules that satisfy all the requirements for a candidate drug to function therapeutically. Therapeutic activity can then be achieved by an understanding of and control over structure and reactivity of the candidate drug through molecular manipulation

A modular self-assembled sensing system for heavy metal ions with tunable sensitivity and selectivity

Here we describe a self-assembled sensing system composed of three separate modules: gold nano particles, a reporter element, and a recognition element. The gold nanoparticles serve as a multivalent platform for the interaction with both the reporter and recognition element and the gold nucleus serves to affect the fluorescent properties of the reporter. The reporter element serves for generation of the output signal. The recognition element serves to make the assay selective. The working principle is that the interaction of the analyte with the recognition element leads to an increased affinity for the gold nanoparticle, which causes a displacement of the reporter and a turn-ON of fluorescence. It is shown that the modular nature of the system permits straightforward tuning of the dynamic detection range, the sensitivity, and the selectivity, simply by changing the recognition module. The system can detect Hg2+ and Ag+ metal ions at nanomolar concentrations in aqueous buffer

High-resolution NMR structure of an RNA model system : the 14-mer cUUCGg tetraloop hairpin RNA

We present a high-resolution nuclear magnetic resonance (NMR) solution structure of a 14-mer RNA hairpin capped by cUUCGg tetraloop. This short and very stable RNA presents an important model system for the study of RNA structure and dynamics using NMR spectroscopy, molecular dynamics (MD) simulations and RNA force-field development. The extraordinary high precision of the structure (root mean square deviation of 0.3 Å) could be achieved by measuring and incorporating all currently accessible NMR parameters, including distances derived from nuclear Overhauser effect (NOE) intensities, torsion-angle dependent homonuclear and heteronuclear scalar coupling constants, projection-angle-dependent cross-correlated relaxation rates and residual dipolar couplings. The structure calculations were performed with the program CNS using the ARIA setup and protocols. The structure quality was further improved by a final refinement in explicit water using OPLS force field parameters for non-bonded interactions and charges. In addition, the 2'-hydroxyl groups have been assigned and their conformation has been analyzed based on NOE contacts. The structure currently defines a benchmark for the precision and accuracy amenable to RNA structure determination by NMR spectroscopy. Here, we discuss the impact of various NMR restraints on structure quality and discuss in detail the dynamics of this system as previously determined

Influence of a fluorobenzene nucleobase analogue on the conformational flexibility of RNA studied by molecular dynamics simulations

Chemically modified bases are frequently used to stabilize nucleic acids, to study the driving forces for nucleic acid structure formation and to tune DNA and RNA hybridization conditions. In particular, fluorobenzene and fluorobenzimidazole base analogues can act as universal bases able to pair with any natural base and to stabilize RNA duplex formation. Although these base analogues are compatible with an A-form RNA geometry, little is known about the influence on the fine structure and conformational dynamics of RNA. In the present study, nano-second molecular dynamics (MD) simulations have been performed to characterize the dynamics of RNA duplexes containing a central 1'-deoxy-1'-(2,4-difluorophenyl)-ß-D-ribofuranose base pair or opposite to an adenine base. For comparison, RNA with a central uridine:adenine pair and a 1'-deoxy-1'-(phenyl)-ß-D-ribofuranose opposite to an adenine was also investigated. The MD simulations indicate a stable overall A-form geometry for the RNAs with base analogues. However, the presence of the base analogues caused a locally enhanced mobility of the central bases inducing mainly base pair shear and opening motions. No stable ‘base-paired’ geometry was found for the base analogue pair or the base analogue:adenine pairs, which explains in part the universal base character of these analogues. Instead, the conformational fluctuations of the base analogues lead to an enhanced accessibility of the bases in the major and minor grooves of the helix compared with a regular base pair