Hydrophobic Arms Research Articles

Photoswitchable Calixarene Activators for Controlled Peptide Transport across Lipid Membranes.

Supramolecular synthetic transporters are crucial to understand and activate the passage across lipid membranes of hydrophilic effector molecules. Herein, we introduce photoswitchable calixarenes for the light-controlled transport activation of cationic peptide cargos across model lipid bilayers and inside living cells. Our approach was based on rationally designed p-sulfonatocalix[4]arene receptors equipped with a hydrophobic azobenzene arm, which recognize cationic peptide sequences at the nM range. Activation of membrane peptide transport is confirmed, in synthetic vesicles and living cells, for calixarene activators featuring the azobenzene arm in the E configuration. Therefore, this method allows the modulation of the transmembrane transport of peptide cargos upon Z-E photoisomerization of functionalized calixarenes using 500 nm visible light. These results showcase the potential of photoswitchable counterion activators for the light-triggered delivery of hydrophilic biomolecules and pave the way for potential applications in remotely controlled membrane transport and photopharmacology applications of hydrophilic functional biomolecules.

Trials and adventures of the synthesis and evaluation of amphiphilic graft copolymers with dynamic topology

AbstractAmphiphilic graft copolymers were prepared via a grafting through approach to yield materials with a hydrophilic backbone and hydrophobic arms. The thermally responsive macromonomers were designed to contain a Diels–Alder adduct such that cyclo‐reversion would cleave the arms from the backbone thus altering polymer topology, composition and solubility. The macromonomers were prepared via light‐inducted atom transfer radical polymerization followed by post‐polymerization modification to install a polymerizable functionality. Next, free radical polymerization was employed to yield thermally responsive amphiphilic graft copolymers, whose solution state characteristics were extensively characterized by UV/Vis spectroscopy and fluorimetry. Due to the amphiphilic nature of the graft copolymer, some unexpected results occurred because of aggregation and solubility limitations. Furthermore, it was discovered that poly(N‐isopropyl acrylamide) exhibited distinct and unique aggregation properties by itself.

Super-paramagnetic polymer composite-supported dendrimer–Mn catalyst: Fabrication, characterization and catalytic evaluation in selective aerobic oxidation of ethylbenzene and oximes derivatives

Design of strategy and catalytic for oxidation ethylbenzene, toxic petroleum, to high value-added via hydrogen-atom-transfer process is lately attracting a renewed interest from both environmentally and economic view. Herein, novel manganese-based dendritic catalysts supported on the polymer-magnetic core-shell were synthesized, fully identified and evaluated with initiator NDHPI for selective and easy-to-handle aerobic oxidation of ethylbenzene (EB) and oximes to acetophenone (ACP) & carbonyl compounds (AH/KO), respectively. Besides mild condition reaction, the supported dendrimer-encapsulated Mn NPs also exhibited outstanding catalytic performance, such as selective oxidation of ethylbenzene and oximes using O2 as green and cheaper oxidant with excellent reactivity, selectivity, stability, and magnetic recyclability. Additionally, the effect of operating parameters such as the amount of catalyst, nature of solvent, temperature and reaction time, and role of several N-hydroxyimides were studied in the catalytic efficiency of the synthesized dendritic catalyst. The results illustrated that the enhanced catalytic efficiency of the catalyst is derived from the magnetic dendritic structures, high Mn(II) content, hydrophobic arm of dendrimers, and interaction of Mn and the dendritic framework. Finally, the reaction pathway for EB and oxime has been deduced, and the crucial role of dendritic catalyst, NDPHI, and electronic effect has been elucidated.

In vivo study of miktoarm star copolymers as a promising nanocarrier to transfer hydrophobic chemotherapeutic agents to breast cancer tumor

In this project, in vitro and in vivo properties of drug loaded nanocarriers based on miktoarm star copolymer mPEG-Lys-PCL2 were evaluated. Miktoarm was synthesized using ring opening polymerization reaction. Then, quercetin which is a hydrophobic plant based flavonol, was loaded into star NCs using nanoprecipitation method. The structure and biocompatibility nanocarriers were determined using proton nuclear magnetic resonance, Fourier-transform infrared spectroscopy, dynamic light scattering, hemolysis assay and lethal dose test. According to biocompatibility tests, prepared nanocarrier was practically nontoxic. The drug loading and encapsulation efficiency of nanocarriers were high because of miktoarm has two hydrophobic arms and more spaces between layers in comparison with linear copolymer with the same material. The results of MTT assay proved that quercetin-loaded star nanocarriers possess acceptable toxicity on cancerous cells which is because of the ability of miktoarm to mimic phospholipid structure. Furthermore, in vivo results showed the quercetin-loaded star nanocarriers is more effective to inhibit tumor volume than the free Quer. Also, the survival rate of mice treated with quercetin loaded star nanocarriers enhanced so that all the treated mice survived more than 75 days, and 20% of them were alive even after 85 days of experiment.

Dimerization-dependent membrane tethering by Atg23 is essential for yeast autophagy.

SUMMARYEukaryotes maintain cellular health through the engulfment and subsequent degradation of intracellular cargo using macroautophagy. The function of Atg23, despite being critical to the efficiency of this process, is unclear due to a lack of biochemical investigations and an absence of any structural information. In this study, we use a combination of in vitro and in vivo methods to show that Atg23 exists primarily as a homodimer, a conformation facilitated by a putative amphipathic helix. We utilize small-angle X-ray scattering to monitor the overall shape of Atg23, revealing that it contains an extended rod-like structure spanning approximately 320 Å. We also demonstrate that Atg23 interacts with membranes directly, primarily through electrostatic interactions, and that these interactions lead to vesicle tethering. Finally, mutation of the hydrophobic face of the putative amphipathic helix completely precludes dimer formation, leading to severely impaired subcellular localization, vesicle tethering, Atg9 binding, and autophagic efficiency.

Facile and Low-Cost Fabrication of a Thread/Paper-Based Wearable System for Simultaneous Detection of Lactate and pH in Human Sweat

Wearable devices have received tremendous interests in human sweat analysis in the past few years. However, the widely used polymeric substrates and the layer-by-layer stacking structures greatly influence the cost-efficiency, conformability and breathability of the devices, further hindering their practical applications. Herein, we report a facile and low-cost strategy for the fabrication of a skin-friendly thread/paper-based wearable system consisting of a sweat reservoir and a multi-sensing component for simultaneous in situ analysis of sweat pH and lactate. In the system, hydrophilic silk thread serves as the micro-channel to guide the liquid flow. Filter papers were functionalized to prepare colorimetric sensors for lactate and pH. The smartphone-based quantitative analysis shows that the sensors are sensitive and reliable. Although pH may interfere the lactate detection, the pH detected simultaneously could be employed to correct the measured data for the achievement of a precise lactate level. After being integrated with a hydrophobic arm guard, the system was successfully used for the on-body measurement of pH and lactate in the sweats secreted from the volunteers. This low-cost, easy-to-fabricate, light-weight and flexible thread/paper-based microfluidic sensing device may hold great potentials as a wearable system in human sweat analysis and point-of-care diagnostics.

Homochiral Metal–Organic Frameworks of Lead(II) and Cadmium(II) Constructed by Amino Acid-Functionalized Isophthalic Acids: Synthesis, Structure Diversity, and Optical Properties

On the basis of amino acid-functionalized isophthalic acids, four interesting homochiral metal–organic frameworks (HMOFs), namely, {[Pb2(HL1)2]·11H2O}n (1), {[Pb2(HL2)2]·12H2O}n (2), {[Cd6(L2)4(H2O)11]·6H2O}n (3), and [Pb(HL3)]n (4), were constructed (H3L1 = (S)-5-(((1-carboxyethyl)amino)methyl)isophthalic acid, H3L2 = (S)-5-(((1-carboxy-3-methylbutyl)amino)methyl)isophthalic acid, and H3L3 = (S)-5-(((1-carboxy-2-phenylethyl)amino)methyl)isophthalic acid). In 1, 2, and 4, all PbII ions have hemidirected coordination geometries despite the difference in coordination number, and ligands H3L1–H3L3 in negative bivalent zwitterionic forms adopt various coordination modes to bridge PbII centers into two- and three-dimensional (2D–3D) coordination polymers, respectively. Both 1 and 2 contain two independent 63-topological homochiral layers which further form a unique hydrogen-bonded double-layered HMOF with the stereochemically active lone pairs of all PbII ions pointing inward and the hydrophobic side arms of amino acid groups being located on both sides. For 4, it is a 3D helicate of (42·6·83)(42·63·8) topology, and the resulting one-dimensional (1D) channels are occupied by the hydrophobic benzyls of amino acid groups in (HL3)2– ligands. Coordination polymer 3 is an intriguing HMOF that contains two independent 2D double-layered (63)(65·8)-topological helicates with alternating distribution of 1D hydrophilic and hydrophobic helical channels. In 3, all hydrophilic helical channels are occupied by water molecules, while all hydrophobic helical channels are filled by the isobutyls of amino acid groups. Remarkably, these chiral tricarboxylic ligands not only have versatile coordination modes in the construction of HMOFs, but also subtly regulate the crystal structures through the different hydrophobic side arms of amino acids implanted in these ligands. Furthermore, the thermal stabilities and solid-state optical properties, including CD spectra, and nonlinear optical and luminescent properties of these complexes were also investigated. Interestingly enough, in our example, it was found that hemidirected, five-coordinate PbII compounds perhaps have stronger emission than those hemidirected four- or six-coordinate PbII compounds.

Thermally stable core-shell star-shaped block copolymers for antifouling enhancement of water purification membranes

Star-shaped block copolymers (SPs), consisting of a hydrophobic core and hydrophilic arms, are a new material architecture introduced to the area of antifouling coatings for water filtration membranes. The unique self-assembly behavior of these SPs on hydrophobic membranes surface allows the formation of an ultrathin coating (less than 15 nm), rendering a highly hydrophilic antifouling membrane surface. Here, we have judiciously examined several important structural and process parameters, such as the chemical composition of SPs and surface properties (e.g., surface potential, coverage, and wettability) driven by a mono- or bi-layered assembly of SPs, to acquire a highly hydrophilic and thermally stable antifouling coating on a hydrophobic ultrafiltration (polysulfone, PSF) membrane for oil sands produced water treatment. Among three types of SPs (e.g., SP1 with 100% amine, SP2 with 55% amine/45% PEG, and SP3 with 35% carboxylic acid/65% PEG moieties in the arms) and their variable coating conditions, the bilayer coating comprised of SP3 top-layer and SP1 bottom-layer exhibited the best hydrophilicity and anti-oil fouling efficiency showing 2–4 times higher water flux compared to an unmodified PSF membrane during the filtration of synthetic oil-water emulsions conducted in both constant flux mode and constant pressure mode. Outstanding antifouling efficiency of the bilayer coating toward natural organic matters (NOMs) was also verified by using bovine serum albumin (BSA) and humic acid (HA) as the model foulants. The bilayer-coated membrane retained more than 80% and 90% (for nano and micron size oil emulsion, respectively) of its initial antifouling efficiency even after rigorous thermal treatment for an extended period (80 °C for 1 week), which demonstrates its feasibility for high-temperature membrane operation.

Transformations of Thermosensitive Hyperbranched Poly(ionic liquid)s Monolayers.

We synthesized amphiphilic hyperbranched poly(ionic liquid)s (HBPILs) with asymmetrical peripheral composition consisting of hydrophobic n-octadecylurethane arms and hydrophilic, ionically linked poly(N-isopropylacrylamide) (PNIPAM) macrocations and studied low critical solution temperature (LCST)-induced reorganizations at the air-water interface. We observed that the morphology of HBPIL Langmuir monolayers is controlled by the surface pressure with uniform well-defined disk-like domains formed in a liquid phase. These domains are merged and transformed to uniform monolayers with elevated ridge-like network structures representing coalesced interdomain boundaries in a solid phase because the branched architecture and asymmetrical chemical composition stabilize the disk-like morphology under high compression. Above LCST, elevated individual islands are formed because of the aggregation of the collapsed hydrophobized PNIPAM terminal macrocations in a solid phase. The presence of thermoresponsive PNIPAM macrocations initiates monolayer reorganization at LCST with transformation of surface mechanical contrast distribution. The heterogeneity of elastic response and adhesion distributions for HBPIL monolayers in the wet state changed from highly contrasted two-phase distribution below LCST to near-uniform mechanical response above LCST because of the hydrophilic to hydrophobic transformation of the PNIPAM phase.

Insight into the antimicrobial mechanism of action of β2,2-amino acid derivatives from molecular dynamics simulation: Dancing the can-can at the membrane surface

The development of antimicrobial agents that target and selectively disrupt biofilms is a pressing issue since, so far, no antibiotics have been developed that achieve this effectively. Previous experimental work has found a promising set of antibacterial peptides: β2,2-amino acid derivatives, relatively small molecules with common structural elements composed of a polar head group and two non-polar hydrocarbon arms. In order to develop insight into possible mechanisms of action of these novel antibacterial agents, we have performed an in silico investigation of four leading β2,2-amino acid derivatives, interacting with models of both bacterial (target) and eukaryotic (host) membranes, using molecular dynamics simulation with a model with all-atom resolution. We found an unexpected result that could shed light on the mechanism of action of these antimicrobial agents: the molecules assume a conformation where one of the hydrophobic arms is directed downward into the membrane core while the other is directed upwards, out of the membrane and exposed above the position of the membrane headgroups; we dubbed this conformation the “can-can pose”. Intriguingly, the can-can pose was most closely linked to the choice of headgroup. Also, the compound previously found to be most effective against biofilms displayed the strongest extent of this behavior and, additionally, this behavior was more pronounced for this compound in the bacterial than in the eukaryotic membrane. We hypothesize that adopting the can-can pose could possibly disrupt the protective peptidoglycan macronet found on the exterior of the bacterial membrane.

High quality fullerene film based on electrophoresis deposition for RRAM device application

Abstract Even though [60]fullerene has excellent electrochemical stability and strong electron affinity, it is barely made into dense-packed film through electrophoresis method in electronic devices. But with the help of the long hydrophobic arms of tetra-n-octyl ammonium bromide in toluene solution, electrophoresis deposition was successfully used as an easy way to fabricate high quality [60]fullerene film on ITO glass substrate. When the composition and thickness of the film were confirmed by IR, XPS and SEM, the resulted film was used as the middle functional layer of RRAM device. After the IV spectra test of memory devices with different thickness of [60]fullerene layer, it was found that the memory character changed from Flash to WORM when the film thickness evolved from 200 nm to 400 nm. This is the first example to study memory performance of uniform C60 film manufactured by the electrophoresis deposition.

A novel strategy to create bifunctional silica-protected quantum dot nanoprobe for fluorescence imaging

Quantum dots (QDs) as fluorescence probes have attracted increasing attention for their fluorescence imaging applications. In this work, we developed a novel strategy to create bifunctional silica-protected QD (BSQD) nanoparticles as nanoprobes for fluorescence imaging. The thiol-ene click reaction of monounsaturated fatty acid salts with mercapto silane as an efficient method for the synthesis of the bifurcated surface modifier was presented. BSQD nanoprobes were prepared by a facile one-pot method. The whole reaction process was carried out in an aqueous solution under relatively low temperature, which makes the synthesis environment eco-friendly and the products cost-effective. The synthesized BSQD nanoprobes have a structure consisting of hydrophilic and hydrophobic arms that afforded an amphiphilic feature to the silica-protected QD (SQD) nanoparticles. The separated solid BSQD nanoprobes could be well dispersed into aqueous solution once again, and the quantum yield of the BSQD nanoprobes was higher than that of the SQD naoprobes. BSQD nanoprobes exhibited high interfacial activity, strong photostability and good biocompatibility. BSQD nanoprobes were successfully applied for fluorescence imaging. The strategy for the construction of the functionalized SQD nanoparticles provides a promising approach for modifying the surface of materials containing QDs.

Y-shaped copolymers of poly(ethylene glycol)-poly(ε-caprolactone) with ketal bond as the branchpoint for drug delivery

In this study, a Y-shaped amphiphilic block copolymer consisting of hydrophilic poly(ethylene glycol) (mPEG) and two poly(ε-caprolactone) (PCL) as the hydrophobic arms with a ketal linker was synthesized (mPEG-Ketal-(PCL)2). The structure of the copolymer with different compositions was characterized by 1H NMR, gel permeation chromatography (GPC) and differential scanning calorimetry (DSC). The amphiphilic property endows the copolymer with the ability to be self-assembled into micelles for encapsulating anticancer drug doxorubicin (DOX), and the effect of copolymer with different PCL length on drug loading properties were tested. The morphology, size, pH responsiveness, drug release profile and in vitro anticancer activity of the DOX loaded micelles were also studied. In vitro drug release studies showed that over 50% of the DOX was released at pH 5.0 in 24 h because of hydrolysis of ketal linker in the copolymers. The confocal laser microscopy and flow cytometry experiments showed that the DOX-loaded micelles could be effectively internalized by Hela cells, the ketal bond in the backbone was broken in acid endo/lysosomal compartments and triggered the fast release of DOX. The in vitro antitumor efficacy of the DOX loaded mPEG-Ketal-(PCL)2 micelles was better than that of non-pH sensitive ones. In vivo studies showed that the mPEG-Ketal-(PCL)2 micelles enhanced the DOX blood circulation time and had good tumor-targeting efficiency.

Shape Transformations of Vesicles Self-Assembled from Amphiphilic Hyperbranched Multiarm Copolymers via Simulation.

The understanding of shape transformations of vesicles is of fundamental importance in biological and clinical sciences. Hyperbranched polymer vesicles (branched polymersomes) are newly emerging polymer vesicles with special structure and property. They have also been regarded as a good model for biomembranes. However, the shape transformations of hyperbranched polymer vesicles have not been studied from either an experimental or theoretical level. Herein, the shape transformations of vesicles self-assembled from amphiphilic hyperbranched multiarm copolymers (HMCs) in response to the interaction parameters between the hydrophobic core and hydrophilic arms and the polymer concentrations are investigated carefully through dissipative particle dynamics (DPD) simulations. In the morphological phase diagram, two types of vesicles are obtained: one type corresponds to vesicles without holes formed at low concentrations including unilamellar vesicles, double-lamellar vesicles, discocyte-shaped vesicles, and tubular vesicles, and the other type corresponds to vesicles with holes formed at high concentrations including stomatocyte-shaped vesicles, toroidal vesicles, genus-3 (G-3) toroidal vesicles with three holes, and genus-4 (G-4) toroidal vesicles with four holes. In addition, both the self-assembly mechanisms and the dynamics for the formation of these vesicles have been systematically studied. The current work will offer theoretical support for fabricating novel vesicles with various shapes from hyperbranched polymers.

A clip-like host that undergoes self-assembly and competitive guest-induced disassembly in water

ABSTRACTCertain calix[4]arenes that are anionic and appended with a single hydrophobic substituent can self-assemble into homodimers in water. The unusual behaviours of these assemblies in water solutions are largely attributed to them being formed from like-charged building blocks. We report here a new entry into this series – a difunctionalized analog with two hydrophobic arms, a net – 3 charge on each monomer, and an overall U-shaped ‘clip’ topology. We use 1H NMR, 1-D DOSY and ITC to show that the new compound dimerizes in water but remains monomeric in organic solvents. Various cationic ammonium ion guests are able to drive dimer disassembly in favor of 1:1 host-guest complexes. The extent of competition is proportional to overall guest hydrophobicity.

Temperature and pH-Dual Responsive AIE-Active Core Crosslinked Polyethylene-Poly(methacrylic acid) Multimiktoarm Star Copolymers.

A series of aggregation-induced emission (AIE) active core crosslinked miktoarm star copolymers, having multi polyethylene (PE) and poly(methacrylic acid) (PMAA) arms, were synthesized and their thermal/pH responsive properties were studied. The procedure involves (a) the synthesis of PE-Br by polyhomologation of dimethylsulfoxonium methylide with triethylborane as initiator, followed by oxidation-hydrolysis/esterification reactions and of poly(tert-butyl methacrylate) (PtBMA-Br) by atom transfer radical polymerization (ATRP) of tert-butyl methacrylate, (b) the synthesis of (PE)n-(PtBMA)m-P(TPE-2St) by ATRP of a double styrene-functionalized tetraphenylethene (TPE-2St) with PE-Br and PtBMA-Br macroinitiators, and (c) the hydrolysis of (PE)n-(PtBMA)m-P(TPE-2St) to afford the amphiphilic miktoarm star copolymers (PE)n-(PMMA)m-P(TPE-2St). Due to their spherical core-shell structure (temperature-responsive) and the presence of hydrophilic PMAA (pH-responsive) and TPE-2St (AIE), these miktoarm star copolymers are AIE materials with temperature/pH-dual responsivity. In addition, thanks to the coexistence of hydrophilic and hydrophobic arms, these materials promote stable water-in-oil emulsions.

Reduction of bacterial attachment on hydroxyapatite surfaces: Using hydrophobicity and chemical functionality to enhance surface retention and prevent attachment.

Water-soluble, linear polymers with high-acid functionality are commonly used in oral care formulations to provide benefits such as bioactive complexation and delivery, as well as inhibition of the bacteria deposition and colonization, commonly referred to as 'anti-attachment'. Unfortunately, structure-activity relationship (SAR) studies of these polymers are scarce, thus, a systematic approach to design polymers with a desired property (e.g. anti-attachment) is limited. Multifunctional anti-attachment amphiphilic molecules (AMs) featuring a sugar backbone, hydrophobic arms, a poly(ethylene glycol) tail, and a chemical anchor effectively deposited on soft ceramic surfaces and reduced bacterial adhesion. The chemical compositions of the AMs were fine-tuned to better coordinate with dental enamel surfaces and prevent bacterial colonization. A graft-to approach was used to investigate the effect of the chemical anchor on AM deposition and retention. The chemical composition, absorption/desorption, and wettability properties of the bioactives and bioactive-coated surfaces were investigated using nuclear magnetic resonance, X-ray photon spectroscopy, quartz crystal microbalance, and contact angle. In addition, the ability of the AMs to provide anti-bacterial attachment on a simulated enamel surface was evaluated in vitro using bacterial repulsion assays. The SAR between surface retention and anti-attachment properties of the AMs demonstrates the feasibility and tunability of using these polymers as bioactive agents that provide anti-attachment benefits on dental enamel surfaces.

Unravelling the Effects of the Mutation m.3571insC/MT-ND1 on Respiratory Complexes Structural Organization.

Mammalian respiratory complex I (CI) biogenesis requires both nuclear and mitochondria-encoded proteins and is mostly organized in respiratory supercomplexes. Among the CI proteins encoded by the mitochondrial DNA, NADH-ubiquinone oxidoreductase chain 1 (ND1) is a core subunit, evolutionary conserved from bacteria to mammals. Recently, ND1 has been recognized as a pivotal subunit in maintaining the structural and functional interaction among the hydrophilic and hydrophobic CI arms. A critical role of human ND1 both in CI biogenesis and in the dynamic organization of supercomplexes has been depicted, although the proof of concept is still missing and the critical amount of ND1 protein necessary for a proper assembly of both CI and supercomplexes is not defined. By exploiting a unique model in which human ND1 is allotopically re-expressed in cells lacking the endogenous protein, we demonstrated that the lack of this protein induces a stall in the multi-step process of CI biogenesis, as well as the alteration of supramolecular organization of respiratory complexes. We also defined a mutation threshold for the m.3571insC truncative mutation in mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 1 (MT-ND1), below which CI and its supramolecular organization is recovered, strengthening the notion that a certain amount of human ND1 is required for CI and supercomplexes biogenesis.

Chaperone‐client interactions between Hsp21 and client proteins monitored in solution by small angle X‐ray scattering and captured by crosslinking mass spectrometry

The small heat shock protein (sHsp) chaperones are important for stress survival, yet the molecular details of how they interact with client proteins are not understood. All sHsps share a folded middle domain to which is appended flexible N- and C-terminal regions varying in length and sequence between different sHsps which, in different ways for different sHsps, mediate recognition of client proteins. In plants there is a chloroplast-localized sHsp, Hsp21, and a structural model suggests that Hsp21 has a dodecameric arrangement with six N-terminal arms located on the outside of the dodecamer and six inwardly-facing. Here, we investigated the interactions between Hsp21 and thermosensitive model substrate client proteins in solution, by small-angle X-ray scattering (SAXS) and crosslinking mass spectrometry. The chaperone-client complexes were monitored and the Rg -values were found to increase continuously during 20 min at 45°, which could reflect binding of partially unfolded clients to the flexible N-terminal arms of the Hsp21 dodecamer. No such increase in Rg -values was observed with a mutational variant of Hsp21, which is mainly dimeric and has reduced chaperone activity. Crosslinking data suggest that the chaperone-client interactions involve the N-terminal region in Hsp21 and only certain parts in the client proteins. These parts are peripheral structural elements presumably the first to unfold under destabilizing conditions. We propose that the flexible and hydrophobic N-terminal arms of Hsp21 can trap and refold early-unfolding intermediates with or without dodecamer dissociation.

A Simple Isomerization of the Purine Scaffold of a Kinase Inhibitor, Roscovitine, Affords a Four- to Seven-Fold Enhancement of Its Affinity for Four CDKs. Could This Be Traced Back to Conjugation-Induced Stiffenings/Loosenings of Rotational Barriers?

Roscovitine is an antitumor purine inhibitor of cyclin-dependent kinase CDK5, for which it displays submicromolar affinity. It reached phase IIb clinical trials in 2007. The search for analogues with improved kinase affinities led recently to an isomer, finisterine, having a nearly 10-fold greater affinity for both CDK5 and CDK9. It solely differs by the displacement of one nitrogen atom in the purine ring, from position 6 to position 9. This has no incidence on the intermolecular interaction of either drug with the neighboring sites that anchor the ring in the recognition site. Quantum chemistry calculations combined with conformational and topological analyses of the impact of the purine ring isomerization of roscovitine and finisterine on its conformational stability show that the modified electronic conjugation, on the other hand, results in a stiffening of the rotational barrier around the extracyclic C–NH bond of finisterine, vicinal to N9, and to which an aryl ring is connected, along with a loosening of the barrier around an extracyclic C6–C bond connecting to a shorter, hydrophobic arm. The first effect is proposed to lead to a lesser hydration entropy of solvation in the case of finisterine, thus to a facilitated desolvation term in the overall energy balances.