Simulations reveal that the HIV-1 gp120-CD4 complex dissociates via complex pathways and is a potential target of the polyamidoamine (PAMAM) dendrimer

The polyamidoamine (PAMAM) dendrimer prevents HIV-1 entry into target cells in vitro. Its mechanism of action, however, remains unclear and precludes the design of potent dendrimers targeting HIV-1 entry. We employed steered molecular dynamics simulations to examine whether the HIV-1 gp120-CD4 complex is a target of PAMAM. Our simulations mimicked single molecule force spectroscopy studies of the unbinding of the gp120-CD4 complex under the influence of a controlled external force. We found that the complex dissociates via complex pathways and defies the standard classification of adhesion molecules as catch and slip bonds. When the force loading rate was large, the complex behaved as a slip bond, weakening gradually. When the loading rate was small, the complex initially strengthened, akin to a catch bond, but eventually dissociated over shorter separations than with large loading rates. PAMAM docked to gp120 and destabilized the gp120-CD4 complex. The rupture force of the complex was lowered by PAMAM. PAMAM disrupted salt bridges and hydrogen bonds across the gp120-CD4 interface and altered the hydration pattern of the hydrophobic cavity in the interface. In addition, intriguingly, PAMAM suppressed the distinction in the dissociation pathways of the complex between the small and large loading rate regimes. Taken together, our simulations reveal that PAMAM targets the gp120-CD4 complex at two levels: it weakens the complex and also alters its dissociation pathway, potentially inhibiting HIV-1 entry.

Efficient Dendrimer-DNA Complexation and Gene Delivery Vector Properties of Nitrogen-Core Poly(propyl ether imine) Dendrimer in Mammalian Cells

Dendrimers as vectors for gene delivery were established, primarily by utilizing few prominent dendrimer types so far. We report herein studies of DNA complexation efficacies and gene delivery vector properties of a nitrogen-core poly(propyl ether imine) (PETIM) dendrimer, constituted with 22 tertiary amine internal branches and 24 primary amines at the periphery. The interaction of the dendrimer with pEGFPDNA was evaluated through UV-vis, circular dichroism (CD) spectral studies, ethidium bromide fluorescence emission quenching, thermal melting, and gel retardation assays, from which most changes to DNA structure during complexation was found to occur at a weight ratio of dendrimer:DNA similar to 2:1. The zeta potential measurements further confirmed this stoichiometry at electroneutrality. The structure of a DNA oligomer upon dendrimer complexation was simulated through molecular modeling and the simulation showed that the dendrimer enfolded DNA oligomer along both major and minor grooves, without causing DNA deformation, in 1:1 and 2:1 dendrimer-to-DNA complexes. Atomic force microscopy (AFM) studies on dendrimer-pEGFP DNA complex showed an increase in the average z-height as a result of dendrimers decorating the DNA, without causing a distortion of the DNA structure. Cytotoxicity studies involving five different mammalian cell lines, using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide] (MTT) assay, reveal the dendrimer toxicity profile (IC50) values of similar to 400-1000 mu g mL(-1), depending on the cell line tested. Quantitative estimation, using luciferase assay, showed that the gene transfection was at least 100 times higher when compared to poly(ethylene imine) branched polymer, having similar number of cationic sites as the dendrimer. The present study establishes the physicochemical behavior of new nitrogen-core PETIM dendrimer-DNA complexes, their lower toxicities, and efficient gene delivery vector properties.

Optical bio-sensing devices based on etched fiber Bragg gratings coated with carbon nanotubes and graphene oxide along with a specific dendrimer

We demonstrate that etched fiber Bragg gratings (eFBGs) coated with single walled carbon nanotubes (SWNTs) and graphene oxide (GO) are highly sensitive and accurate biochemical sensors. Here, for detecting protein concanavalin A (Con A), mannose-functionalized poly(propyl ether imine) (PETIM) dendrimers (DMs) have been attached to the SWNTs (or GO) coated on the surface modified eFBG. The dendrimers act as multivalent ligands, having specificity to detect lectin Con A. The specificity of the sensor is shown by a much weaker response (factor of similar to 2500 for the SWNT and similar to 2000 for the GO coated eFBG) to detect non specific lectin peanut agglutinin. DM molecules functionalized GO coated eFBG sensors showed excellent specificity to Con A even in the presence of excess amount of an interfering protein bovine serum albumin. The shift in the Bragg wavelength (Delta lambda(B)) with respect to the lambda(B) values of SWNT (or GO)-DM coated eFBG for various concentrations of lectin follows Langmuir type adsorption isotherm, giving an affinity constant of similar to 4 x 10(7) M-1 for SWNTs coated eFBG and similar to 3 x 10(8) M-1 for the GO coated eFBG. (C) 2014 Elsevier B.V. All rights reserved.

The SPL7013 dendrimer destabilizes the HIV-1 gp120-CD4 complex

The poly (l-lysine)-based SPL7013 dendrimer with naphthalene disulphonate surface groups blocks the entry of HIV-1 into target cells and is in clinical trials for development as a topical microbicide. Its mechanism of action against R5 HIV-1, the HIV-1 variant implicated in transmission across individuals, remains poorly understood. Using docking and fully atomistic MD simulations, we find that SPL7013 binds tightly to R5 gp120 in the gp120-CD4 complex but weakly to gp120 alone. Further, the binding, although to multiple regions of gp120, does not occlude the CD4 binding site on gp120, suggesting that SPL7013 does not prevent the binding of R5 gp120 to CD4. Using MD simulations to compute binding energies of several docked structures, we find that SPL7013 binding to gp120 significantly weakens the gp120-CD4 complex. Finally, we use steered molecular dynamics (SMD) to study the kinetics of the dissociation of the gp120-CD4 complex in the absence of the dendrimer and with the dendrimer bound in each of the several stable configurations to gp120. We find that SPL7013 significantly lowers the force required to rupture the gp120-CD4 complex and accelerates its dissociation. Taken together, our findings suggest that SPL7013 compromises the stability of the R5 gp120-CD4 complex, potentially preventing the accrual of the requisite number of gp120-CD4 complexes across the virus-cell interface, thereby blocking virus entry.

A dendrimer facilitates resonance energy transfer between hydrophobic aromatic guest molecules in water

A water soluble third generation poly(alkyl aryl ether) dendrimer was examined for its ability to solubilize hydrophobic polyaromatic molecules in water and facilitate non-radiative resonance energy transfer between them. One to two orders of magnitude higher aqueous solubilities of pyrene (PY), perylene (PE), acridine yellow (AY) and acridine orange (AO) were observed in presence of a defined concentration of the dendrimer. A reduction in the quantum yield of the donor PY* emission and a partial decrease in lifetime of the donor excited state revealed the occurrence of energy transfer from dendrimer solubilized excited PY to ground state PE molecules, both present within a dendrimer. The energy transfer efficiency was estimated to be similar to 61%. A cascade resonance energy transfer in a three component system, PY*-to-PE-to-AY and PY*-to-PE-to-AO, was demonstrated through incorporation of AY or AO in the two component PY-PE system. In the three-component system, excitation of PY resulted in emission from AY or AO via a cascade energy transfer process. Careful choice of dye molecules with good spectral overlap and the employment of dendrimer as the medium enabled us to expand absorption-emission wavelengths, from similar to 330 nm to similar to 600 nm in aqueous solution. (C) 2015 Elsevier B.V. All rights reserved.

Dendrimer films as matrices for electrochemical fabrication of novel gold/palladium bimetallic nanostructures

Electrodeposition of novel Au/Pd bimetallic nanostructures with dendrimer films as matrices has been reported. The dendrimers exhibited highly open structures arising from protonation of amines and this made them have good penetrability for solvent molecules. The unique properties of dendrimers obviously affected the morphologies and compositions of deposited bimetallic nanostructures compared with those from unmodified surfaces. Field-emitted scanning electron microscopy, energy dispersive spectroscopy, X-ray photoelectron spectroscopy and UV-vis spectroscopy were used to characterize these nanostructures.

A sensitive impedimetric thrombin aptasensor based on polyamidoamine dendrimer

A label-free and highly sensitive impedimetric aptasensor based on a polyamidoamine dendrimer modified gold electrode was developed for the determination of thrombin. Amino-terminated polyamidoamine dendrimer was firstly covalently attached to the cysteine functionalized gold electrode through glutaraldehyde coupling. Subsequently, the dendrimer was activated with glutaraldehyde, and amino-modified thrombin aptamer probe was immobilized onto the activated dendrimer monolayer film. The layer-by-layer assembly process was traced by surface plasmon resonance and electrochemical impedance spectroscopy.

Electrochemical impedance detection of DNA hybridization based on dendrimer modified electrode

Bioactive ultrathin films with the incorporation of amino-terminated G4 PAMAM dendrimers have been prepared via layer-by-layer self-assembly methods on a gold electrode and used for the DNA hybridization analysis. Surface plasmon resonance (SPR), X-ray photoelectron spectroscopy (XPS), and electrochemical impedance spectroscopy (EIS) are used to characterize the successful construction of the multicomponent film on the gold substrate. The dendrimer-modified surfaces improve the immobilization capacity of the probe DNA greatly, compared to the AET (2aminoethanethiol) SAM sensor surfaces without dendrimer molecules. DNA hybridization analysis is monitored by EIS. The dendrimer-based electrochemical impedance DNA biosensor shows high sensitivity and selectivity for DNA hybridization assay. The multicomponent films also display a high stability during repeated regeneration and hybridization cycles.

One-step preparation and characterization of poly(propyleneimine) dendrimer-protected silver nanoclusters

Highly stable silver nanoclusters with narrow size distribution have been prepared by heating a third-generation poly(propyleneimine) dendrimer/AgNO3 aqueous solution without the additional step of introducing other reducing agents and protect agents. UV-vis absorption, transmission electron microscopy (TEM), X-ray photoelectron spectra (XPS), and X-ray diffraction (XRD) have been used to characterize the resulting products. The as-obtained sample was in coexistence of Ag and Ag2O. It also suggested that increasing temperature resulted in both the decrease in number of small particles and the increase in size of large particles.

Carboxyl-cored dendrimer and toluene-assisted fabrication of uniform platinum nanodendrites at a water/oil interface and their potential application as a catalyst

Uniform platinum nanodendrites have been prepared at a water/oil interface by a facile catalyst-free method at room temperature. This is carried out by introducing NaBH4 into the platinum precursor solution in the presence of the second generation of carboxyl-cored dendrimer ([G-2]-CO2H dendrimer) and toluene to act as a protective agent and a linker, respectively. The average fractal dimension of 1.61 of the obtained platinum nanodendrites is calculated by analysing the transmission electron micrographs using the programs Fractal Dimension Version 1.1 and Fractal Dimension Calculator. Control experiments show that the fabrication of platinum nanodendrites can be operated with a wide parameter window, which undoubtedly raises the degree of control of the synthesis process. The potential application of such a nanostructure as a catalyst is investigated, and the results reveal that they show highly efficient catalytic properties for the typical redox reaction between hexacyanoferrate (III) and thiosulfate ions at 301 K.

Room-temperature strategy for networked nonspherical gold nanostructures from Au(III)-[G-2]-CO2H dendrimer complex

The present work describes a convenient approach to fabricate networked nonspherical gold nanostructures by using [G-2]-CO2H dendrimer and toluene as capping and bridging agents in a CH2Cl2 and H2O biphasic system. A controlled linear assembly is achieved without the use of any catalyst at room temperature. UV-vis spectrum, transmission electron microscopy (TEM), selected area electron diffraction (SAED), and X-ray diffraction (XRD) analysis show that the product is well networked nanostructures with diameter of 4-10 nm and consists of coalesced face-centered cubic gold nanocrystals. Extended experiments reveal that both benzene and dimethylbenzene can also inhabit the gold ions to make them crosslinked, prolong the nucleation points and eventually facilitate the formation of the networks.

Bright electroluminescence from a new conjugated dendrimer

Photoluminescence and electroluminescence from a new conjugated dendrimer consisting of three distyrylbenzene units linked by a central nitrogen atom as core and meta-linked biphenyl units as dendrons were investigated. Bright electroluminescence was realized by using bilayer devices with blurred interface, which were fabricated by sequentially spin-coating a neat dendrimer and a dendrimer doped with 2-(4-biphenyl)-5-(4-tert-butylphenyl)-1,3,4-oxadiazole (PBD). By optimizing the concentration of PBD, the maximum brightness and EL quantum efficiency reach 4100 cd/m(2) and 0.10%, respectively.

One-step synthesis and size control of dendrimer-protected gold nanoparticles: A heat-treatment-based strategy

Dendrimer-protected gold nanoparticles have been facilely obtained by heating an aqueous solution containing third generation poly(propyleneimine) dendrimers and HAuCl4 without the additional step of introducing other reducing agents. Transmission electron microscopy (TEM) and UV vis data indicate the size the nucleation and growth kinetics of gold nanoparticles thus formed which can be tuned by changing the initial molar ratio of dendrimer to gold.