Supramolecular layer-by-layer assembly: alternating adsorptions of guest- and host-functionalized molecules and particles using multivalent supramolecular interactions

The stepwise construction of a novel kind of self-assembled organic/inorganic multilayers based on multivalent supramolecular interactions between guest-functionalized dendrimers and host-modified gold nanoparticles has been developed, yielding supramolecular layer-by-layer assembly. The deposition process was monitored by surface plasmon resonance spectroscopy. Further characterization of the multilayer films was performed by means of UV/vis absorption spectroscopy, which showed a linear increase in absorption with the number of bilayers. The growth of the gold nanoparticle plasmon absorption band corresponded to approximately a dense monolayer of gold nanoparticles per bilayer. Ellipsometry and atomic force microscopy (AFM) scratching experiments were used to measure the development of the film thickness with the number of bilayers, confirming linear growth and a thickness increase of approximately 2 nm/bilayer.     

Arene-anion based arginine-binding motif on a galactose scaffold: structure-activity relationships of interactions with arginine-rich galectins

Two series of C3-benzamido and O2-anion-substituted galactopyranosides were synthesized and studied as binders to arginine-rich proteins galectin-1, -3, -7, -8N (N-terminal domain), and -9N (N-terminal domain). The first series had a 4-methylbenzamide at C3 and the anionic O2-substituent was varied. The second series varied the 4-substituent of the C3-benzamide, whereas the anionic O2 substituent was kept as a sulfate. The influence of the O2-anion substituent correlated negatively with the oxygen charge density in case of galectin-1, -3, and -9N. In the second series, the electron-donating capacity of the 4-substituent of the C3-benzamides correlated positively with the magnitude of the affinity enhancement by the 2O-sulfate.     

Stable hairpins with beta-peptides: route to tackle protein-protein interactions

Experimental and theoretical data demonstrate that sequences of heterochiral beta (2,3)-amino acids and a turn-inducing beta-dipeptide adopt hairpin-like structures in methanol. On the basis of extensive canonical and replica exchange MD simulations, we could transfer these findings to water as the solvent of physiological relevance. We show that rationally designed beta-peptides exhibit a higher folding tendency and a more robust hairpin structure formation in water compared with alpha-peptides. Furthermore, our designed scaffold enables the addition of a wide variety of functions without disrupting the structure. Since hairpins are often involved in protein interactions, the very stable hairpin-like fold of our designed beta-peptides might be used as a lead scaffold for the design of molecules that specifically modulate protein-protein interactions. This is demonstrated by application of this concept to the recognition of proline-rich sequences (PRS) by WW domains, an important interaction in cell signaling. We focus on the possibility to imitate the strands 2 and 3 of any WW domain as a minimal motif to recognize their target sequences PPXY. We conclude that rationally designed beta-peptide hairpins can serve as scaffolds not only to tackle PPII recognition but also to open up a way to influence a wide variety of protein-protein interactions.     

Peptide inhibitors of viral assembly: a novel route to broad-spectrum antivirals

We investigated the potential of small peptide segments to function as broad-spectrum antiviral drug leads. We extracted the α-helical peptide segments that share common secondary-structure environments in the capsid protein-protein interfaces of three unrelated virus classes (PRD1-like, HK97-like, and BTV-like) that encompass different levels of pathogenicity to humans, animals, and plants. The potential for the binding of these peptides to the individual capsid proteins was then investigated using blind docking simulations. Most of the extracted α-helical peptides were found to interact favorably with one or more of the protein-protein interfaces within the capsid in all three classes of virus. Moreover, binding of these peptides to the interface regions was found to block one or more of the putative "hot spot" regions on the protein interface, thereby providing the potential to disrupt virus capsid assembly via competitive interaction with other capsid proteins. In particular, binding of the GDFNALSN peptide was found to block interface "hot spot" regions in most of the viruses, providing a potential lead for broad-spectrum antiviral drug therapy.     

Synthesis of polyhydroxy piperidines and their analogues: a novel approach towards selective inhibitors of alpha-glucosidase

Various polyhydroxy piperidine azasugars have been synthesized from precursors 18a and 18b, obtained in both enantiomeric forms from d-ribose. Out of these polyhydroxy piperidine azasugars, 22, 39 and 20 were found to be potent as well as selective inhibitors of alpha-glucosidase with K(i) values ranging as low as 1.07 microM, 16.4 microM, and 88.2 microM, respectively. Replacement of the hydroxy methylene moiety of (K(i) 33% at 1 mM) by an amino methylene moiety (32, K(i) 36.8 microM) showed a remarkable increase in the activity (almost 30 times). Furthermore, increasing the lipophilicity of by N-alkylation with a dodecyl group (36) showed a three-fold enhancement in the activity (K(i) 217 microM to K(i) 72.3 microM).     

Specific interactions of complementary mono- and multivalent guests with recognition-induced polymersomes

We have explored the interactions of mono- and multivalent guests with Recognition-Induced Polymersomes (RIPs) formed from complementary random copolymers featuring diamidopyridine and thymine functionality. Addition of monovalent guests featuring imide functionality to these RIPs induced a temporary swelling of the vesicles, followed by dissociation of the vesicles due to competitive binding of the guest. Conversely, multivalent thymine-functionalized nanoparticle guests were rapidly incorporated into the RIPs, inducing a contraction of RIP diameter over time. These mono- and multivalent interactions were extremely specific: highly analogous control systems showed no interaction with the RIP structures. Taken together, these studies demonstrate highly selective molecular "lock and key" control over higher-order assembly and recognition processes.     

Modification of resonance light scattering spectra of silver nanoparticles due to their interactions with protein molecules

Regularities of changes in resonance light scattering spectra of silver nanoparticles due to their interactions with protein molecules are studied. This effect can be used to identify biological molecules and elucidate their modification, in particular those due to oxidative processes, using optical techniques.     

Perfluoroalkylation of simple inorganic molecules: a one step route to novel perfluoroalkylated compounds

Reactions of (CH3)3SiRf (Rf = CF3, C2F5) with NOCl, NO/NO2, SO2, CO2, in the presence of caesium fluoride provide a one step synthetic route to perfluoroalkylated compounds in very good yields.     

Synthesis of some oligopyridine-galactose conjugates and their metal complexes: a simple entry to multivalent sugar ligands

Some galactose-oligopyridine conjugates were readily assembled by combining differently functionalized oligopyridines with peracetylated galactose derivatives. Variation in the structure of the components and of the linkers employed for their connection afforded adducts of different size, shape, and conformational mobility. Complexation of the bipyridine ligands with CuOTf and of the terpyridine ligand with Zn(OTf)₂ afforded the corresponding peracetylated 2:1 and 1:1 complexes, respectively, as single species. Their structures were determined to be tetrahedral (Cu complexes) and trigonal-bipyramidal (Zn complex), on the basis of spectroscopic evidence. Removal of the acetyl protecting groups from the ligands afforded the corresponding polyols. The terpyridine-Zn(II) complex, unlike the bipyridine-Cu(I) complexes maintained their structures upon removal of the acetyl protecting groups.     

Het(aryl)isatin to het(aryl)aminoindoline scaffold hopping: A route to selective inhibitors of matrix metalloproteinases

Matrix metalloproteinases (MMPs) are a large family of zinc-dependent endoproteases known to exert multiple regulatory roles in tumor progression. A variety of chemical classes have been explored for targeting individual MMP isoforms. In the present study, we further developed our isatin based scaffold BB0223107 capable of binding to and inactivating MMP-2 in a zinc-independent manner (Agamennone et al., 2016). Forty four new compounds were synthesized based on the modified BB0223107. All compounds were tested in enzyme inhibition assays against MMP-2, ?8 and ?13. SAR studies demonstrated that 5-het(aryl)-3-aminoindolin-2-ones (37–39) were active toward MMP-2 and MMP-13. The most potent compounds 33 and 37 displayed an IC₅₀ of 3 µM against MMP-13 and showed a negligible activity toward MMP-8; almost all new compounds were inactive toward MMP-8. Replacement of the isatin ring with a biaryl system (compound 33) did not decrease the potency against MMP-13 but reduced the selectivity. Structure-based computational studies were carried out to rationalize the inhibitory activity data. The analysis of binding geometries confirmed that all fragments occupied the S1′ site in the three enzymes while no ligand was able to bind the catalytic zinc ion. To the best of our knowledge, this is the first example of 3-aminoindolin-2-one-based MMP inhibitors that, based on the computer modeling study, do not coordinate the zinc ion. Thus, the het(aryl)-3-aminoindolin-2-one derivatives emerge as a drug-like and promising chemotype that, along with the hetaryl variations, represents an alternative and thrifty tool for chemical space exploration aimed at MMP inhibitor design.     

Activation of CdS nanoparticles by metallic ions and their selective interactions with PAMAM dendrimers

CdS nanoparticles (NPs) in colloidal dispersion were activated by metallic ions [Mn(II) and Cu(II)], employing a simple method under mild conditions. These metallic ions on the surface of the CdS NPs quench the red-shifted defect emission, and efficiently promote near band gap emission; they also enhance the photo stability and dispersability of the suspensions. Taking advantage of the chemical affinity of Mn(II) and Cu(II) for the CdS surface, we carried out a study of the interaction between [CdS-M(II) _n ] NPs and polyamidoamine dendrimers of 1 and 2.5 generations (G₁=8 amino, and G_2.5=32 carboxylic end-groups, respectively). The strong interaction between these two chemical species results in the formation of new [CdS-M(II) _n G _n ] nanocomposites. All colloidal systems were monitored by UV-visible electronic absorption and emission spectroscopies, and electronic paramagnetic resonance. The crystal structures of the nanocomposites, as well as their average diameters (2.0–3.3 nm), were determined by high-resolution transmission electron microscopy images.     

Hierarchical interactions and their influence upon the adsorption of organic molecules on a graphene film

The competition between intermolecular interactions and lateral variations in the molecule-substrate interactions has been studied by scanning tunneling microscopy (STM), comparing the phase formation of (sub)monolayers of the organic molecule 2,4'-BTP on buckled graphene/Ru(0001) and Ag(111) oriented thin films on Ru(0001). On the Ag films, the molecules form a densely packed 2D structure, while on graphene/Ru(0001), only the areas between the maxima are populated. The findings are rationalized by a high corrugation in the adsorption potential for 2,4'-BTP molecules on graphene/Ru(0001). These findings are supported by temperature programmed desorption (TPD) experiments and theoretical results.     

Use of inverse gas chromatography to characterize cotton fabrics and their interactions with fragrance molecules at controlled relative humidity

The present work focused on the surface characterization and fragrance interactions of a common cotton towel at different relative humidities (RHs) using inverse gas chromatography (IGC) and dynamic vapour sorption. The sigmoidal water sorption isotherms showed a maximum of 16% (w/w) water uptake with limited swelling at 100% RH. This means that water interacts strongly with cotton and might change its initial physico-chemical properties. The same cotton towel was then packed in a glass column and characterized by IGC at different relative humidities, calculating the dispersive and specific surface energy components. The dispersive component of the surface energy decreases slightly as a function of relative humidity (42 mJ/m2 at 0% RH to 36 mJ/m2 at 80% RH) which would be expected from swelling of the humidified cotton. The Gutmann's donor constant Kd increased from 0.28 kJ/mol at 0% RH to 0.42 kJ/mol at 80% RH, indicating that a greater hydrophilic surface exists at 80% RH, which is also as expected. Water, undecane and four fragrance molecules (dimetol, benzyl acetate, decanal and phenylethanol) were used to investigate cotton-fragrance interactions between 0 and 80% RH. The adsorption enthalpies and the Henry's constants were calculated and are discussed. The higher values for the adsorption enthalpies of polar molecules such as dimetol and phenylethanol suggest the presence of hydrogen bonds as the main adsorption mechanism. The Henry's constant of dimetol was also determined by headspace gas chromatography measurements at 20% RH, giving a similar value (230 nmol/Pa g by IGC and 130 nmol/Pa g by headspace GC), supporting the usefulness of IGC for such determinations. This work confirms the usefulness of chromatographic methods to investigate biopolymers such as textiles, starches and hairs.     

AMBER: Assisted model building with energy refinement. A general program for modeling molecules and their interactions

We describe a computer program we have been developing to build models of molecules and calculate their interactions using empirical energy approaches. The program is sufficiently flexible and general to allow modeling of small molecules, as well as polymers. As an illustration, we present applications of the program to study the conformation of actinomycin D. In particular, we study the rotational isomerism about the D -Val-, L -Pro, and L -Pro-Sar amide bonds as well as comparing the energy and structure of the Sobell model and the x-ray structure of actinomycin D.     

High-avidity,low-affinity multivalent interactions and the block to polyspermy in Xenopus laevis

The interaction of the lectin XL35 with the jelly coat protein (JCP) surrounding oocytes in Xenopus laevis is essential for the block to polyspermy. The molecular details of this event are poorly understood, and the present study has been undertaken with a view to delineating the mechanism of formation of the fertilization envelope. A range of JCP-derived oligosaccharides were synthesized, and all were installed with an artificial aminopropyl arm. This arm allowed the preparation of monovalent derivatives by acetylation of the amino group or the synthesis of polyvalent compounds by attachment to an activated polyacrylamide polymer. A number of analytical techniques, including enzyme-linked lectin assays and surface plasmon resonance, have been developed and utilized to study the interactions of the mono- and polyvalent compounds with XL35. The results reveal that the lectin XL35 has remarkably broad specificity for galactose-containing saccharides and the affinities are only slightly modulated by secondary features, such as anomeric configuration of the terminal sugar or the identity and linkage pattern of branching sugars. Broad specificity was also observed when the saccharides were presented in a polyvalent fashion. The glycopolymers displayed 10-20-fold increases in valency-corrected affinities compared to the corresponding monovalent counterparts. Although the synthetic polymers are not as potent as the JCP, the kinetics of their interactions mirror closely those of the native ligand, and in each case extremely long-lived interactions were observed. The results of this study indicate that, in X. laevis, the true biological function of multivalency is not to create an extremely tightly binding complex between XL35 and its natural ligand but, instead, to create a very stable protective layer that will not dissociate and is yet flexible enough to encapsulate the developing embryo. It is postulated that, even if these partners are unable to attain true equilibrium on the time scale of the biological event, their mode of interaction would, nevertheless, be expected to guarantee an insurmountable physical block to polyspermy. This study has also highlighted that multivalent interactions require a very long time to achieve equilibrium, and this feature may well be the origin of several of the ambiguities reported in the literature when multivalent ligands have been evaluated.     

Layer-by-layer self-assembly of multilayer films containing DNA and Eu3+: their characteristics and interactions with small molecules

Thin films of alternating DNA and rare earth ion Eu3+ layers from dilute aqueous solutions were fabricated onto quartz substrates and silicon wafers through the layer-by-layer (LbL) self-assembly technique. UV-visible spectroscopy shows that a uniform layer of DNA can be fully adsorbed onto each alternate Eu3+ layer. Microscopic FTIR spectra show Eu3+ interacts with both the phosphate groups and nitrogenous bases of DNA, and the formation of [DNA/Eu]n films induces a change of the conformation of the DNA secondary structure to a certain extent. Various parameters affecting the DNA or Eu3+ loading into the composite film were investigated with emphasis on the effect of the pH and ionic strength of the DNA solution used for the film preparation. Atomic force microscopy was utilized to observe the morphologies of the DNA in the films obtained at two different pH values. Small molecules, such as alpha-tenoyltrifluoroacetone (TTA), Hoechst 33258 (Hoe), and ethidium bromide (EB), are all observed to interact with Eu3+ or DNA in the [DNA/Eu]n films. The [DNA/Eu]n films incorporated with these molecules show different fluorescent characteristics, and the fluorescence intensity of the films versus the bilayer number has a good linear relationship, confirming the potential for creating a different luminescence ability of the multilayer by controlling the number of DNA/Eu bilayers.