Mihail Barboiu

Dynamic hybrid materials for constitutional self-instructed membranes.

Constitutional self-instructed membranes were developed and used for mimicking the adaptive structural functionality of natural ion-channel systems. These membranes are based on dynamic hybrid materials in which the functional self-organized macrocycles are reversibly connected with the inorganic silica through hydrophobic noncovalent interactions. Supramolecular columnar ion-channel architectures can be generated by reversible confinement within scaffolding hydrophobic silica mesopores. They can be structurally determined by using X-ray diffraction and morphologically tuned by alkali-salts templating. From the conceptual point of view, these membranes express a synergistic adaptive behavior: the simultaneous binding of the fittest cation and its anion would be a case of “homotropic allosteric interactions,” because in time it increases the transport efficiency of the pore-contained superstructures by a selective evolving process toward the fittest ion channel. The hybrid membranes presented here represent dynamic constitutional systems evolving over time to form the fittest ion channels from a library of molecular and supramolecular components, or selecting the fittest ion pairs from a mixture of salts demonstrating flexible adaptation.

Artificial Water Channels

Water is fundamental to life, playing a variety of functions related to its complex dynamic behavior at the supramolecular level. Most of the physiological processes depend on the selective exchange of ions or molecules between a cell and its environment, with water playing a crucial role in their translocation events. Artificial ion channels have been extensively studied with the hope of facilitating ionic conduction in bilayer membranes. However, there has been less progress in the area of synthetic water channels. In contrast to spherical ions, dipolar water molecules shed light on the inherent multiple interactions with biological environments through the combination of weak reversible bonds, namely hydrogen bonding, salt bridges, dipolar, and coordinative interactions. Moreover, the overall dipolar orientation of assembled water dipoles is of tremendous importance in the regulation of the selective transport of charged components across the cell membrane. For example, encapsulated water wires of opposite dipolar orientation control the electrochemical potential selectively along the aquaporin pore Aqp channel, thereby allowing the rapid diffusion of water, while protons and ions are excluded. The water permeability of Aqp-incorporated polymeric vesicles has been at least an order of magnitude larger than values obtained for classical polymeric membranes. Moreover, it has been shown that about five water molecules may flow per nanosecond through carbon nanotube membranes under an osmotic gradient comparable to those measured for biological water channels. Finally, the one-dimensional water wires have attracted a lot interest, and selective proton gating is the key function of the influenza A M2 proton channel. Different water clusters have been entrapped within complex superstructures. They have attracted a lot interest in terms of a variety of fundamental processes such as water structuration and also in the context of special aspects of water–cluster interactions with the host matrix or diffusional phenomena under confined conditions. Despite such an impressive development, only a few artificial hydrophobic, hydrophilic, and hybrid amphiphilic pores have been designed to selectively transport water very efficiently through bilayer membranes. Water transport across phospholipid vesicles can be monitored using optical microscopy or dynamic light scattering. The molecular-scale hydrodynamics of water through the channel will depend on channel–water and water–water interactions as well as on the in-pore electrostatic dipolar profile of the water within the channel. The diffusion of water and facilitated transport of protons with exclusion of the transport of other cations and anions through bilayer membranes were reported for the first time by Percec et al. The dendritic dipeptides 1 (Figure 1a) selfassemble through enhanced peripheral p stacking to form stable helical pores in bilayers. These pores, envisioned as “primitive aquaporins”, transport water but do not exclude protons. The ion-exclusion phenomena are based on hydrophobic effects which appear to be very important. Later, Barboiu and co-workers reported that imidazole (I) quartets can be mutually stabilized by inner dipolar water wires, reminiscent of G-quartets stabilized by cation templating. The I-quartets are stable in solution, in the solid state, and within bilayers, leading to the tubular channel-type chiral superstructures. These systems have provided excellent reasons to consider that the supramolecular chirality of Iquartets and water-induced polarization within the channels may be strongly associated. The confined water wires, similar to the situation in aquaporin channels, form one hydrogen bond with the inner wall of the I-quartet and one hydrogen bond with an adjacent water molecule. Moreover, the water molecules adopt a unique dipolar orientation and preserve the overall electrochemical dipolar potential along the channel. These results strongly indicate that water molecules and protons can permeate the bilayer membranes through Iquartet channels. The ion-exclusion phenomena are based on dimensional steric effects, whereas hydrophobic and hydrodynamic effects appear to be less important. The water-free “off form” superstructure of the I-quartet is reminiscent of the closed conformation of the proton gate of the influenza A M2 protein. The slight conformational adjustments allow formation of the water-templated I-quartet, through which protons can diffuse along a dipolar oriented water wire in the open-state pore–gate region. These artificial I-quartet superstructures obtained by using a simple chemical approach are in excellent agreement with structural X-ray and NMR spectroscopic results as well as theoretical results that might provide accurate mechanistic explanations for water/proton conductance through the influenza A M2 proton channel. In a very recent report Hou and co-workers proposed a very elegant artificial system that functions exclusively as single-molecular water channels. Polydrazide-substituted pillar[5]arenes were used to form tubular hydrogen-bonded [*] Dr. M. Barboiu Adaptive Supramolecular Nanosystems Group Institut Europeen des Membranes, ENSCM-UMII-UMR CNRS 5635 Place Eugene Bataillon CC047, 34095 Montpellier (France) E-mail: mihai.barboiu@iemm.univ-montp2.fr . Angewandte Highlights

Supramolecular self-organization in constitutional hybrid materials

We present in this paper a new strategy to transcribe the supramolecular dynamic self-organization of the G-quadruplex and ureidocrown ether ion channel-type columnar architectures in constitutional hybrids. In particular, the use of a “dynamic reversible hydrophobic interface” can render the emerging hybrid mesophases self-adaptive. The reversible hydrophobic interactions allow both supramolecular and inorganic silica components to mutually (synergistically) adapt their spatial constitution during simultaneous (collective) formation of micrometric self-organized hybrid domains. More generally, applying such consideration to materials, leads to the definition of constitutional hybrid materials, in which organic (supramolecular)/inorganic domains are reversibly connected. This might provide new insights into the features that control the design of functional materials.

Out-of-Water Constitutional Self-Organization of Chitosan–Cinnamaldehyde Dynagels

An investigation of the constitutional adaptive gelation process of chitosan/cinnamaldehyde (C/Cy) dynagels is reported. These gels generate timely variant macroscopic organization across extended scales. In the first stage, imine-bond formation takes place in-water and generates low-ordered hydrogels. The progressive formation of imine bonds further induces out-of-water increased reactivity within interdigitated hydrophobic self-assembled layers of Cy, with a protecting environmental effect against hydrolysis and that leads to the stabilization of the imine bonds. The hydrophobic swelling due to Cy layers at the interfaces reaches a critical step when lamellar self-organized hybrids are generated (24u2005hours). This induces an important restructuration of the hydrogels on the micrometric scale, thus resulting in the formation of highly ordered microporous xerogel morphologies of high potential interest for chemical separations, drug delivery, and sensors.

Constitutional dynamic chemistry

Jean-Marie Lehn Constitutional Dynamic Chemistry: Bridge from Supramolecular Chemistry to Adaptive Chemistry.- Mihail Barboiu Multistate and Phase Change Selection in Constitutional Multivalent Systems.- Morakot Sakulsombat Yan Zhang Olof Ramstrom Dynamic Systemic Resolution.- Emilie Moulin Nicolas Giuseppone Dynamic Combinatorial Self-Replicating Systems.- Benjamin L. Miller DCC in the Development of Nucleic Acid Targeted and Nucleic Acid Inspired Structures.- Eugene Mahon Teodor Aastrup Mihail Barboiu Dynamic Nanoplatforms in Biosensor and Membrane Constitutional Systems.- D. Quemener A. Deratani S. Lecommandoux Dynamic Assembly of Block-Copolymers.- Radu Custelcean Dynamic Chemistry of Anion Recognition.- Nandhini Ponnuswamy Artur R. Stefankiewicz Jeremy K. M. Sanders G. Dan Pantos Supramolecular Naphthalenediimide Nanotubes.- Adrian-Mihail Stadler Juan Ramirez Synthetic Molecular Machines and Polymer/Monomer Size Switches that Operate Through Dynamic and Non-Dynamic Covalent Changes Kamel Meguellati Sylvain Ladame Reversible Covalent Chemistries Compatible with the Principles of Constitutional Dynamic Chemistry: New Reactions to Create More Diversity.

Multistate and Phase Change Selection in Constitutional Multivalent Systems

Molecular architectures and materials can be constitutionally self-sorted in the presence of different biomolecular targets or external physical stimuli or chemical effectors, thus responding to an external selection pressure. The high selectivity and specificity of different bioreceptors or self-correlated internal interactions may be used to describe the complex constitutional behaviors through multistate component selection from a dynamic library. The self-selection may result in the dynamic amplification of self-optimized architectures during the phase change process. The sol-gel resolution of dynamic molecular/supramolecular libraries leads to higher self-organized constitutional hybrid materials, in which organic (supramolecular)/inorganic domains are reversibily connected.

Salt-Excluding Artificial Water Channels Exhibiting Enhanced Dipolar Water and Proton Translocation

Aquaporins (AQPs) are biological water channels known for fast water transport (∼10(8)-10(9) molecules/s/channel) with ion exclusion. Few synthetic channels have been designed to mimic this high water permeability, and none reject ions at a significant level. Selective water translocation has previously been shown to depend on water-wires spanning the AQP pore that reverse their orientation, combined with correlated channel motions. No quantitative correlation between the dipolar orientation of the water-wires and their effects on water and proton translocation has been reported. Here, we use complementary X-ray structural data, bilayer transport experiments, and molecular dynamics (MD) simulations to gain key insights and quantify transport. We report artificial imidazole-quartet water channels with 2.6 Å pores, similar to AQP channels, that encapsulate oriented dipolar water-wires in a confined chiral conduit. These channels are able to transport ∼10(6) water molecules/s, which is within 2 orders of magnitude of AQPs rates, and reject all ions except protons. The proton conductance is high (∼5 H(+)/s/channel) and approximately half that of the M2 proton channel at neutral pH. Chirality is a key feature influencing channel efficiency.

A class of carbonic anhydrase I – selective activators

Abstract A series of ureido and bis-ureido derivatives were prepared by reacting histamine with alkyl/aryl-isocyanates or di-isocyanates. The obtained derivatives were assayed as activators of the enzyme carbonic anhydrase (CA, EC 4.2.1.1), due to the fact that histamine itself has this biological activity. Although inhibition of CAs has pharmacological applications in the field of antiglaucoma, anticonvulsant, anticancer, and anti-infective agents, activation of these enzymes is not yet properly exploited pharmacologically for cognitive enhancement or Alzheimer’s disease treatment, conditions in which a diminished CA activity was reported. The ureido/bis-ureido histamine derivatives investigated here showed activating effects only against the cytosolic human (h) isoform hCA I, having no effect on the widespread, physiologically dominant isoform hCA II. This is the first report in which CA I-selective activators were identified. Such compounds may constitute interesting tools for better understanding the physiological/pharmacological effects connected to activation of this widespread CA isoform, whose physiological function is not fully understood.

Squalyl Crown Ether Self-Assembled Conjugates: An Example of Highly Selective Artificial K(+) Channels.

The natural KcsA K+ channel, one of the best-characterized biological pore structures, conducts K+ cations at high rates while excluding Na+ cations. The KcsA K+ channel is of primordial inspiration for the design of artificial channels. Important progress in improving conduction activity and K+ /Na+ selectivity has been achieved with artificial ion-channel systems. However, simple artificial systems exhibiting K+ /Na+ selectivity and mimicking the biofunctions of the KcsA K+ channel are unknown. Herein, an artificial ion channel formed by H-bonded stacks of squalyl crown ethers, in which K+ conduction is highly preferred to Na+ conduction, is reported. The K+ -channel behavior is interpreted as arising from discreet stacks of dimers resulting in the formation of oligomeric channels, in which transport of cations occurs through macrocycles mixed with dimeric carriers undergoing dynamic exchange within the bilayer membrane. The present highly K+ -selective macrocyclic channel can be regarded as a biomimetic alternative to the KcsA channel.

Columnar Self-Assemblies of Triarylamines as Scaffolds for Artificial Biomimetic Channels for Ion and for Water Transport

Triarylamine molecules appended with crown-ethers or carboxylic moieties form self-assembled supramolecular channels within lipid bilayers. Fluorescence assays and voltage clamp studies reveal that the self-assemblies incorporating the crown ethers work as single channels for the selective transport of K+ or Rb+. The X-ray crystallographic structures confirm the mutual columnar self-assembly of triarylamines and crown-ethers. The dimensional fit of K+ cations within the 18-crown-6 leads to a partial dehydration and to the formation of alternating K+ cation-water wires within the channel. This original type of organization may be regarded as a biomimetic alternative of columnar K+-water wires observed for the natural KcsA channel. Supramolecular columnar arrangement was also shown for the triarylamine-carboxylic acid conjugate. In this latter case, stopped-flow light scattering analysis reveals the transport of water across lipid bilayer membranes with a relative water permeability as high as 17 μm s-1.