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The effect of lipid composition on models of the inner leaflet of mammalian cell membranes has been investigated. Grazing incidence X-ray diffraction and X-ray and neutron reflectivity have been used to characterize lipid packing and solvation, while electrochemical and infrared spectroscopic methods have been employed to probe phase behavior in an applied electric field. Introducing a small quantity of the anionic lipid dimyristoylphosphatidylserine (DMPS) into bilayers of zwitterionic dimyristoylphosphatidylethanolamine (DMPE) results in a significant change in the bilayer response to an applied field: the tilt of the hydrocarbon chains increases before returning to the original tilt angle on detachment of the bilayer. Equimolar mixtures, with slightly closer chain packing, exhibit a similar but weaker response. The latter also tend to incorporate more solvent during this electrochemical phase transition, at levels similar to those of pure DMPS. Reflectivity measurements reveal greater solvation of lipid layers for DMPS > 30 mol %, matching the greater propensity for DMPS-rich bilayers to incorporate water. Taken together, the data indicate that the range of 10-35 mol % DMPS provides optimum bilayer properties (in flexibility and function as a barrier), which may explain why the DMPS content of cell membranes tends to be found within this range.
Asunto(s)
Membrana Dobles de Lípidos , Mamíferos , Animales , Membrana Dobles de Lípidos/química , Membrana Celular , Espectrofotometría Infrarroja , Membranas , Difracción de Rayos XRESUMEN
Sphingolipids are an important class of lipids found in mammalian cell membranes with important structural and signaling roles. They differ from another major group of lipids, the glycerophospholipids, in the connection of their hydrocarbon chains to their headgroups. In this study, a combination of electrochemical and structural methods has been used to elucidate the effect of this difference on sphingolipid behavior in an applied electric field. N-Palmitoyl sphingomyelin forms bilayers of similar coverage and thickness to its close analogue di-palmitoyl phosphatidylcholine. Grazing incidence diffraction data show slightly closer packing and a smaller chain tilt angle from the surface normal. Electrochemical IR results at low charge density show that the difference in tilt angle is retained on deposition to form bilayers. The bilayers respond differently to increasing electric field strength: chain tilt angles increase for both molecules, but sphingomyelin chains remain tilted as field strength is further increased. This behavior is correlated with disruption of the hydrogen-bonding network of small groups of sphingomyelin molecules, which may have significance for the behavior of molecules in lipid rafts in the presence of strong fields induced by ion gradients or asymmetric distribution of charged lipids.
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Membrana Dobles de Lípidos , Esfingomielinas , Animales , Esfingomielinas/química , Membrana Dobles de Lípidos/química , Fosfatidilcolinas , Membrana Celular , Microdominios de Membrana , MamíferosRESUMEN
Lipid bilayers form the basis of biological cell membranes, selective and responsive barriers vital to the function of the cell. The structure and function of the bilayer are controlled by interactions between the constituent molecules and so vary with the composition of the membrane. These interactions also influence how a membrane behaves in the presence of electric fields they frequently experience in nature. In this study, we characterize the electrochemical phase behavior of dipalmitoylphosphatidylcholine (DPPC), a glycerophospholipid prevalent in nature and often used in model systems and healthcare applications. DPPC bilayers were formed on Au(111) electrodes using Langmuir-Blodgett and Langmuir-Schaefer deposition and studied with electrochemical methods, atomic force microscopy (AFM) and in situ polarization-modulated infrared reflection absorption spectroscopy (PM-IRRAS). The coverage of the substrate determined with AFM is in accord with that estimated from differential capacitance measurements, and the bilayer thickness is slightly higher than for bilayers of the similar but shorter-chained lipid, dimyristoylphosphatidylcholine (DMPC). DPPC bilayers exhibit similar electrochemical response to DMPC bilayers, but the organization of molecules differs, particularly at negative charge densities. Infrared spectra show that DPPC chains tilt as the charge density on the metal is increased in the negative direction, but, unlike in DMPC, the chains then return to their original tilt angle at the most negative potentials. The onset of the increase in the chain tilt angle coincides with a decrease in solvation around the ester carbonyl groups, and the conformation around the acyl chain linkage differs from that in DMPC. We interpret the differences in behavior between bilayers formed from these structurally similar lipids in terms of stronger dispersion forces between DPPC chains and conclude that relatively subtle changes in molecular structure may have a significant impact on a membrane's response to its environment.
Asunto(s)
Oro , Fosfolípidos , 1,2-Dipalmitoilfosfatidilcolina , Dimiristoilfosfatidilcolina , Membrana Dobles de Lípidos , Estructura Molecular , Espectrofotometría InfrarrojaRESUMEN
The efficacy of a number of different methods for depositing a dimyristoylphosphatidylcholine (DMPC) lipid bilayer or DMPC-cholesterol (3 : 1) mixed bilayer onto a silicon substrate has been investigated in a quantitative manner using atomic force microscopy (AFM) image analysis to extract surface coverage. Complementary AFM-IR measurements were used to confirm the presence of the lipids. For the Langmuir-Blodgett/Schaefer deposition method at temperatures below the chain-melting transition temperature (T m), a large number of bilayer defects resulted when DMPC was deposited from a water subphase. Addition of calcium ions to the trough led to smaller, more frequent defects, whereas addition of cholesterol to the lipid mixture led to a vast improvement in bilayer coverage. Poor coverage was achieved for deposition at temperatures above T m. Formation of the deposited bilayer from vesicle fusion proved a more reliable method for all systems, with formation of near-complete bilayers within 60 seconds at temperatures above T m, although this method led to a higher probability of multilayer formation and rougher bilayer surfaces.
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Four new bis-substituted ferrocene derivatives containing either a hydroxyalkyl or methoxyalkyl group and either a thyminyl or methylthyminyl group have been synthesised and characterised by a range of spectroscopic and analytical techniques. They were included in a structure-activity-relationship (SAR) study probing anticancer activities in osteosarcoma (bone cancer) cell lines and were compared with a known lead compound, 1-(S,Rp ), a nucleoside analogue that is highly toxic to cancer cells. Biological studies using the MTT assay revealed that a regioisomer of ferronucleoside 1-(S,Rp ), which only differs from the lead compound in being substituted on two cyclopentadienyl rings rather than one, was over 20â times less cytotoxic. On the other hand, methylated derivatives of 1-(S,Rp ) showed comparable cytotoxicities to the lead compound. Overall these studies indicate that a mechanism of action for 1-(S,Rp ) cannot proceed through alcohol phosphorylation and that its geometry and size, rather than any particular functional group, are crucial factors in explaining its high anticancer activity.
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Antineoplásicos/farmacología , Neoplasias Óseas/tratamiento farmacológico , Compuestos Ferrosos/farmacología , Metalocenos/farmacología , Nucleósidos/farmacología , Compuestos Organometálicos/farmacología , Osteosarcoma/tratamiento farmacológico , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias Óseas/patología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Compuestos Ferrosos/química , Humanos , Metalocenos/química , Metilación , Modelos Moleculares , Estructura Molecular , Nucleósidos/química , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Osteosarcoma/patología , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
A new chiral organometallic nucleoside analogue containing ruthenocene is reported, in which alkylthymine and alkylhydroxyl groups are attached in adjacent positions on one cyclopentadienyl ring. The synthetic procedures for this metallocene derivative and two control compounds are described, along with their characterisation by cyclic voltammetry and X-ray crystallography. Their biological activities in a human pancreatic cancer cell line (MIA-Pa-Ca-2) were significantly lower than those of three previously reported analogous ferrocene compounds, indicating that the choice of metallocene metal atom (Fe or Ru) plays a pivotal role in determining the anticancer properties of these nucleoside analogues, which in turn suggests a different mode of action from that of a conventional nucleoside analogue.
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Antineoplásicos/química , Antineoplásicos/farmacología , Metalocenos/química , Metalocenos/farmacología , Nucleósidos/química , Línea Celular Tumoral , Electroquímica , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Conformación MolecularRESUMEN
The dynamic interactions of membranes, particularly their fusion and fission, are critical for the transmission of chemical information between cells. Fusion is primarily driven by membrane tension built up through membrane deformation. For artificial polymersomes, fusion is commonly induced via the external application of a force field. Herein, fusion-promoted development of anisotropic tubular polymersomes (tubesomes) was achieved in the absence of an external force by exploiting the unique features of aqueous ring-opening metathesis polymerization-induced self-assembly (ROMPISA). The out-of-equilibrium tubesome morphology was found to arise spontaneously during polymerization, and the composition of each tubesome sample (purity and length distribution) could be manipulated simply by targeting different core-block degrees of polymerization (DPs). The evolution of tubesomes was shown to occur via fusion of "monomeric" spherical polymersomes, evidenced most notably by a step-growth-like relationship between the fraction of tubular to spherical nano-objects and the average number of fused particles per tubesome (analogous to monomer conversion and DP, respectively). Fusion was also confirmed by Förster resonance energy transfer (FRET) studies to show membrane blending and confocal microscopy imaging to show mixing of the polymersome lumens. We term this unique phenomenon polymerization-induced polymersome fusion, which operates via the buildup of membrane tension exerted by the growing polymer chains. Given the growing body of evidence demonstrating the importance of nanoparticle shape on biological activity, our methodology provides a facile route to reproducibly obtain samples containing mixtures of spherical and tubular polymersomes, or pure samples of tubesomes, of programmed length. Moreover, the capability to mix the interior aqueous compartments of polymersomes during polymerization-induced fusion also presents opportunities for its application in catalysis, small molecule trafficking, and drug delivery.
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Complejos de Coordinación/síntesis química , Polímeros/síntesis química , Anisotropía , Complejos de Coordinación/química , Transferencia Resonante de Energía de Fluorescencia , Estructura Molecular , Tamaño de la Partícula , Polimerizacion , Polímeros/química , Propiedades de SuperficieRESUMEN
The direct incorporation of macrocyclic cyclidene complexes into DNA via automated synthesis results in a new family of metal-functionalized DNA derivatives that readily demonstrate their utility through the ability of one redox-active copper(II)-containing strand to distinguish electrochemically between all four canonical DNA nucleobases at a single site within a target sequence of DNA.
Asunto(s)
ADN/química , Técnicas Electroquímicas , Compuestos Macrocíclicos/química , Nucleótidos/análisis , Compuestos Organometálicos/química , Estructura MolecularRESUMEN
Differences in molecular organization of two sides of a chemically symmetric, planar bilayer supported on a Au(111) substrate have been monitored with charge density measurements and in situ polarization modulation infrared reflection-absorption spectroscopy (PM-IRRAS). Isotopic substitution of the hydrogen atoms in the hydrocarbon chains with deuterium atoms in one monolayer was employed to allow the monitoring of C-H vibrations from that monolayer alone. Charge density measurements of bilayers formed from dimyristoylphosphatidylethanolamine (DMPE) showed that the effect of placing the deuterated layer next to the substrate or electrolyte had little impact on the electrical barrier properties. In situ PM-IRRAS studies revealed that the structure of the two monolayers was the same at negative potentials, where the bilayer is separated from the Au substrate, but different at more positive potentials or small charge densities, where the bilayer is expected to be directly adsorbed on the Au surface. Thus, the differences observed for the related molecule dimyristoylphosphatidylcholine (DMPC) persist in planar structures, although to a lesser extent. A small but observable variation in the tilt angle was also apparent in the spectra of both isotopically asymmetric DMPE bilayers during the electrochemical phase transition. The fact that this effect was not previously observed for hydrogenous bilayers means that the dynamic behavior of deuterated DMPE and/or of bilayers composed of different monolayers is different from that of hydrogenous DMPE bilayers. These results have implications for future studies in which isotopic substitution is used to extract selectively information from one layer or component of lipid bilayers in spectroscopic or neutron measurements.
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Deuterio/química , Dimiristoilfosfatidilcolina/química , Oro/química , Hidrógeno/química , Membrana Dobles de Lípidos/química , Medición de Intercambio de Deuterio , Técnicas Electroquímicas , Transición de Fase , Espectrofotometría Infrarroja/métodos , Electricidad Estática , Propiedades de SuperficieRESUMEN
A new open-source parallel genetic algorithm, the Birmingham parallel genetic algorithm, is introduced for the direct density functional theory global optimisation of metallic nanoparticles. The program utilises a pool genetic algorithm methodology for the efficient use of massively parallel computational resources. The scaling capability of the Birmingham parallel genetic algorithm is demonstrated through its application to the global optimisation of iridium clusters with 10 to 20 atoms, a catalytically important system with interesting size-specific effects. This is the first study of its type on Iridium clusters of this size and the parallel algorithm is shown to be capable of scaling beyond previous size restrictions and accurately characterising the structures of these larger system sizes. By globally optimising the system directly at the density functional level of theory, the code captures the cubic structures commonly found in sub-nanometre sized Ir clusters.
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A new series of chiral ureas containing one or two redox-active ferrocene units was synthesised and studied in order to investigate the effect of planar chirality and central chirality on electrochemical chiral sensing. Binding of chiral carboxylate anions in organic solvents through H-bond formation caused a negative shift in the potentials of the ferrocene/ferrocenium (Fc/Fc(+)) couples of the receptors, demonstrating their use as electrochemical sensors in solution. While the presence of two ferrocene units gave no marked improvement in the chiral sensing capabilities of these systems, the introduction of planar chirality, in addition to central chirality, switched the enantiomeric binding preference of the system and also caused an interesting change in the appearance of some voltammograms, with unusual two-wave behaviour observed upon binding a protected prolinate guest.
RESUMEN
The global optimization of PdnIr(N-n) N = 8-10 clusters has been performed using the Birmingham Cluster Genetic Algorithm (BCGA). Structures were evaluated directly using density functional theory (DFT), which has allowed the identification of Ir and Ir-rich PdIr cubic global minima, displaying a strong tendency to segregate. The ability of the searches to find the putative global minimum has been assessed using a homotop search method, which shows a high degree of success. The role of spin in the system has been considered through a series of spin-restricted reoptimizations of BCGA-DFT minima. The preferred spin of the clusters is found to vary widely with composition, showing no overall trend in lowest-energy multiplicities.
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In this work we address the challenge of furthering our understanding of the driving forces responsible for the metal-metal interactions in industrially relevant bimetallic nanocatalysts, by taking a comparative approach to the atomic scale characterization of two core-shell nanorod systems (AuPd and AuRh). Using aberration-corrected scanning transmission electron microscopy, we show the existence of a randomly mixed alloy layer some 4-5 atomic layers thick between completely bulk immiscible Au and Rh, which facilitates fully epitaxial overgrowth for the first few atomic layers. In marked contrast in AuPd nanorods, we find atomically sharp segregation resulting in a quasi-epitaxial, strained interface between bulk miscible metals. By comparing the two systems, including molecular dynamics simulations, we are able to gain insights into the factors that may have influenced their structure and chemical ordering, which cannot be explained by the key structural and energetic parameters of either system in isolation, thus demonstrating the advantage of taking a comparative approach to the characterization of complex binary systems. This work highlights the importance of achieving a fundamental understanding of reaction kinetics in realizing the atomically controlled synthesis of bimetallic nanocatalysts.
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A method for the preparation of smooth deposits of Pt on Au nanorods is described, involving sequential deposition steps with selective blocking of surface sites that reduces Pt-on-Pt deposition. The Au-Pt nanorods prepared by this method have higher long-term stability than those prepared by standard Pt deposition. Electrochemical data show that the resulting structure has more extended regions of Pt surface and enhanced activity toward the carbon monoxide oxidation and oxygen reduction reactions.
RESUMEN
The effect of molecular structure on ensemble structure of phospholipid films has been investigated. Bilayers of dimyristoyl phosphatidylethanolamine (DMPE) were prepared on Au(111) electrodes using Langmuir-Blodgett and Langmuir-Schaeffer deposition. Capacitance and charge density measurements were used to investigate the adsorption behavior and barrier properties of the lipid bilayers. In situ polarization modulation infrared reflection absorption spectroscopy (PM-IRRAS) was employed to investigate the organization of the molecules within the bilayer. DMPE bilayers exhibit lower capacitance than bilayers formed from the related lipid, dimyristoyl phosphatidylcholine (DMPC). The infrared data show that these results can be explained by structural differences between the bilayers formed from each molecule. DMPE organizes into bilayers with hydrocarbon chains tilted at a smaller angle to the surface normal, which results in a thicker film. The hydrocarbon chains contain few conformational defects. Spectra in the carbonyl and phosphate stretching mode regions indicate low solvent content of DMPE films. Both of these effects combine to produce films with lower capacitance and enhanced barrier properties. The results are explained in terms of the differences in structure between the constituent molecules.
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Dimiristoilfosfatidilcolina/química , Campos Electromagnéticos , Membrana Dobles de Lípidos/química , Fosfatidiletanolaminas/química , Química Física , Técnicas Electroquímicas , Electrodos , Oro/química , Membrana Dobles de Lípidos/síntesis química , Tamaño de la Partícula , Propiedades de SuperficieRESUMEN
The design, synthesis and electrochemical behaviour of an oligomer consisting of linked thymine-functionalised ferrocene units are reported, which, as a so-called form of ferrocene nucleic acid (FcNA), acts as a structural mimic of DNA.
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Materiales Biomiméticos/química , ADN/química , Compuestos Ferrosos/química , Compuestos Organometálicos/química , Polímeros/química , Materiales Biomiméticos/síntesis química , Metalocenos , Modelos Moleculares , Conformación Molecular , Polímeros/síntesis químicaRESUMEN
This study focuses on the deposition and growth mode of rhodium (Rh) on gold (Au) seed nanorods (NRs). Using a combination of scanning transmission electron microscopy imaging, energy-dispersive X-ray spectroscopy, and UV-visible absorption spectroscopy, we show that Rh deposition results in an uneven overlayer morphology on the Au NR seeds, with a tendency for Rh deposition to occur preferentially on the Au NR ends. The results suggest that complex and kinetically driven metal-metal interactions take place in this system.
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Isolipoic acid, a symmetrical and achiral isomer of the commonly used alpha-lipoic acid, has previously been overlooked as a tether group for the formation of self-assembled monolayers (SAMs). Here its ready synthesis through a new route and its functionalization with ferrocenyl groups for redox-active SAM formation on gold electrodes are described.
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Charge density measurements and polarization modulation infrared reflection absorption spectroscopy were employed to investigate the spreading of small unilamellar vesicles of a dimyristoylphosphatidylcholine (DMPC)/cholesterol (7:3 molar ratio) mixture onto an Au (111) electrode surface. The electrochemical experiments demonstrated that vesicles fuse and spread onto the Au (111) electrode surface, forming a bilayer, at rational potentials -0.4 V < (E - Epzc) < 0.4 V or field strength <6 x 10(7) V m(-1). Polarization modulation infrared reflection absorption spectroscopy experiments provided information concerning the conformation and orientation of the acyl chains of DMPC molecules. Deuterated DMPC was used to subtract the contribution of C-H stretching bands of cholesterol and of the polar head region of DMPC from spectra in the C-H stretching region. The absorption spectra of the C-H stretch bands in the acyl chains were determined in this way. The properties of the DMPC/cholesterol bilayer have been compared with the properties of a pure DMPC bilayer. The presence of 30% cholesterol gives a thicker and more fluid bilayer characterized by a lower capacity and lower tilt angle of the acyl chains.
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Colesterol/química , Electroquímica/métodos , Oro/química , Membrana Dobles de Lípidos/química , Espectrofotometría/métodos , Carbono/química , Dimiristoilfosfatidilcolina/química , Electroquímica/instrumentación , Electrodos , Hidrógeno/química , Lípidos/química , Fluidez de la Membrana , Péptidos/química , Fosfatidilcolinas/química , Espectrofotometría Infrarroja , Espectroscopía Infrarroja por Transformada de Fourier , Propiedades de SuperficieRESUMEN
Hydroxide adsorption on the (111), (110), and (100) faces of silver electrodes from mixed NaOH/NaF solution is studied using cyclic voltammetry and in situ second harmonic generation (SHG). Cyclic voltammograms for the three low index silver planes in alkaline electrolytes are for the first time compared. They show two pairs of anodic and cathodic peaks in the potential interval below the equilibrium Ag/Ag(2)O potential. These are attributed to the specific adsorption of hydroxide ions followed by submonolayer oxide formation. The differences in the cyclic voltammograms for the (111), (110), and (100) planes are attributed to different (i) work functions, (ii) surface atomic densities, and (iii) corrugation potentials for these surfaces. Ex situ low energy electron diffraction (LEED) and reflection high energy electron diffraction (RHEED) show that disordered adlayers are formed on Ag(111) and Ag(100), in contrast to Ag(110), where ordered structures are produced in the region of the first pair of current peaks. In the region of the second pair of peaks, LEED indicates disordered oxide phases on each crystal plane and RHEED shows the presence of small islands of c(2 x 2) structure at some potentials on (110) and (100). SHG measurements were performed (i) in the potential scan mode at constant rotational angle and (ii) at constant potential as a function of the rotational angle. The isotropic (for the (111), (110), and (100) planes) and anisotropic (for the (110) and (111) planes) contributions to the SHG intensity were calculated by fitting the experimental data and are discussed in terms of their dependence on the charge density at the interface, on hydroxide adsorption, and on submonolayer oxide formation.