Sliding tethered ligands add topological interactions to the toolbox of ligand-receptor design.

Adhesion in the biological realm is mediated by specific lock-and-key interactions between ligand-receptor pairs. These complementary moieties are ubiquitously anchored to substrates by tethers that control the interaction range and the mobility of the ligands and receptors, thus tuning the kinetics and strength of the binding events. Here we add sliding anchoring to the toolbox of ligand-receptor design by developing a family of tethered ligands for which the spacer can slide at the anchoring point. Our results show that this additional sliding degree of freedom changes the nature of the adhesive contact by extending the spatial range over which binding may sustain a significant force. By introducing sliding tethered ligands with self-regulating length, this work paves the way for the development of versatile and reusable bio-adhesive substrates with potential applications for drug delivery and tissue engineering.

Dynamic lipid lateral segregation driven by lauryl cyclodextrin interactions at the membrane surface.

Amphiphilic cyclodextrins, with a cholesterol anchor (ßChol) or an aspartic acid moiety esterified by two lauryl acyl chains (ßDLC), were designed to combine the inclusion ability of the cyclodextrin cavity with the carrier properties of model membranes. Their insertion in phosphatidylcholine bilayers induces a marked lateral phase separation into a pure lipid phase and a cyclodextrin-rich phase (LCD), organized as a 2D cyclodextrin network stabilized by intermolecular hydrogen bonds between the saccharide headgroups at the membrane surface (Roux, M.; Perly, B.; Djedaïni-Pilard, F. Self-Assemblies of Amphiphilic Cyclodextrins. Eur. Biophys. J.2007, 36, 861-867). We have replaced the dilauryl anchor by a single lauryl chain grafted onto a leucine residue, giving monolauryl-ß-cyclodextrin (ßMLC), which readily inserts into bilayers of chain-deuterated DMPC-d27. The removal of one lauryl acyl chain leads to a dynamic membrane insertion of this new cyclodextrin derivative, with significant lipid exchange on the deuterium NMR time scale between a loosely packed cyclodextrin-enriched phase (L'CD) and free lipid regions, yielding broadened two-component NMR spectra. Like the LCD phases, the cyclodextrin-enriched L'CD regions remain (partially) fluid below the DMPC-d27 main fluid-to-gel transition but do not undergo a clear transition toward a gel state, as observed at 14.5 °C in the LCD phase induced by the dilauryl derivative. Partially fluid lipids of the ßMLC-induced L'CD phase coexist with pure lipids in the Pß' gel phase with possible exchange between them until all of the lipids undergo a transition toward an Lß' gel state at around 7 °C. Trimethylated monolauryl-ß-cyclodextrins induce only an ordering of the lipid acyl chains just above the main transition, without any lateral phase separation. Similar chain ordering is also observed within the ßMLC-induced L'CD phase as a consequence of the deep membrane insertion of the monolauryl nonmethylated cyclodextrin derivative.

Amphiphilic behavior of new cholesteryl cyclodextrins: a molecular study.

Amphiphilic cyclodextrins (CDs) are good candidates to functionalize natural membranes as well as synthetic vesicles. In this paper, we describe the synthesis of the amphiphilic permethylated monocholesteryl α-CD (TASC). Its interfacial behavior is compared with that of the permethylated mono- and dicholesteryl ß-CD analogues (TBSC and TBdSC). Langmuir isotherms suggest a reorganization upon compression for all compounds, which is quantified using neutron as well as X-ray reflectivity. The in-plane structure is characterized by atomic force microscopy (AFM) on monolayers deposited on solid substrates. A model involving a reorientation of the CD with respect to the interface to adjust its conformation to the available area per molecule is proposed. Although we observe for TBSC a rearrangement similar to TASC and TBdSC, it is already achieved at lower surface pressures compared with its disubstituted derivative. This specific behavior is explained by an increased structural flexibility and compressibility compared with TBdSC and TASC. The average number of water molecules per CD was determined using the neutron data and validated from X-ray data, which also allows the determination of the CD's molecular volume. The permethylated CD molecules are strongly hydrated in the film, but the α-CD analogue is less hydrated than the ß-CD derivatives, and hydration decreases with compression.

Amphiphilic behavior and membrane solubility of a dicholesteryl-cyclodextrin.

Amphiphilic cyclodextrins (CDs) are good candidates to functionalize natural membranes as well as synthetic vesicles. In this paper, we provide a full description of the interfacial behavior of pure 6I,6IV-(ß-cholesteryl)succinylamido-6I,6IV-(6-deoxy-per-(2,3,6-O-methyl))cycloheptaose (TBdSC) and how it inserts in dipalmitoyl-l-α-phosphatidylcholine (DPPC) monolayers as a membrane model. Langmuir isotherms of pure TBdSC suggest a reorganization upon compression, which could be clarified using X-ray reflectivity. The CD head can adjust its conformation to the available area per molecule. A compatible model involving a rotation around a horizontal axis defined by the two selectively substituted glucose units is proposed. The in-plane structure is characterized at all scales by Brewster angle microscopy (BAM) on the water surface and atomic force microscopy (AFM) on monolayers deposited on solid substrates. The same tools are used for its mixtures with DPPC. We show in particular that TBdSC seems to be soluble in the liquid-expanded DPPC. However, phase segregation occurs at higher pressure, allowing for sequentially liquid-condensed DPPC and high-pressure conformation of TBdSC. This gives rise to a remarkable contrast inversion in both imaging methods.

Physico-chemical investigation of asymmetrical peptidolipidyl-cyclodextrins.

A new class of amphiphilic peptidolipidyl-cyclodextrins is reported. The derivatives are chiral due to the presence of an L-leucine in the spacer arm that links a saccharide moiety and a grafted, saturated hydrocarbon chain. Self-assembly properties of the peptidolipidyl-cyclodextrins are characterized by quasi-elastic light scattering, turbidity and UV-visible absorption measurements. NMR experiments give insight into the intermolecular dipolar interactions as a function of temperature and concentration. N-dodecyl-N alpha-(6 I-amidosuccinyl-6 1-deoxy-cyclomaltoheptaose)-L-leucine (1) is poorly soluble in aqueous media. N-dodecyl-N(alpha)-(6 I-amidosuccinyl-6 I-deoxy-2 I,3 I-di-O-methyl-hexakis-(2 II-VII,3 II-VII,6 II-VII-tri-O-methyl)-cyclomaltoheptaose)-L-leucine (2) is found to be more soluble and self-assembles into stable supramolecular colloidal aggregates with nanometric dimensions above a critical aggregation concentration (CAC). It has a propensity for solubilization of hydrophobic species revealing a micellar-like behavior, which is compared to that of the non-ionic detergent octyl glucoside. On the contrary, compound 1 precipitates in a crystalline phase beyond its water solubility limit, and it does not display any solubilizing capacity. The observed behavior corroborates at the molecular level with the NMR results.

Ionic complexation properties of per(3,6-anhydro)cyclodextrin derivatives towards lanthanides.

Using per(3,6-anhydro)cyclodextrin derivatives [per(3,6-anhydro)CD], it was possible to produce new lanthanide chelates by careful choice of the size and functional groups. Heptakis(3,6-anhydro-2-O-methyl)cyclomaltoheptaose fulfils the best criteria for complexation of lanthanide ions. Nuclear magnetic resonance was used to derive the association constants and the stoichiometries of these new complexes. Finally, a three-dimensional structure of these complexes consistent with the NMR data is proposed, to ascertain the position of lanthanide in the cavity of the per(3,6-anhydro)CD. For the present purposes, heptakis(2-O-acetyl-3,6-anhydro)cyclomaltoheptaose, octakis(2-O-acetyl-3,6-anhydro)cyclomaltooctaose, heptakis(3,6-anhydro-2-O-methyl)cyclomaltoheptaose and octakis(3,6-anhydro-2-O-methyl)cyclomaltooctaose have been synthesized and purified.