RESUMEN
Dispersing carbon nanomaterials in solvents is effective in transferring their significant mechanical and functional properties to polymers and nanocomposites. However, poor dispersion of carbon nanomaterials impedes exploiting their full potential in nanocomposites. Cellulose nanocrystals (CNCs) are promising for dispersing and stabilizing pristine carbon nanotubes (pCNTs) and graphene nanoplatelets (pGnP) in protic media without functionalization. Here, the underlying mechanisms at the molecular level are investigated between CNC and pCNT/pGnP that stabilize their dispersion in polar solvents. Based on the spectroscopy and microscopy characterization of CNCpCNT/pGnP and density functional theory (DFT) calculations, an additional intermolecular mechanism is proposed between CNC and pCNT/pGnP that forms carbonoxygen covalent bonds between hydroxyl end groups of CNCs and the defected sites of pCNTs/pGnPs preventing re-agglomeration in polar solvents. This work's findings indicate that the CNC-assisted process enables new capabilities in harnessing nanostructures at the molecular level and tailoring the performance of nanocomposites at higher length scales.
Asunto(s)
Nanocompuestos , Nanopartículas , Nanotubos de Carbono , Celulosa/química , Nanocompuestos/química , Nanopartículas/química , Solventes , AguaRESUMEN
The discovery of tetrazine click-induced secondary interactions is reported as a promising new tool for polymeric biomaterial synthesis. This phenomenon is first demonstrated as a tool for poly(ethylene glycol) (PEG) hydrogel assembly via purely non-covalent interactions and is shown to yield robust gels with storage moduli one to two orders of magnitude higher than other non-covalent crosslinking methods. In addition, tetrazine click-induced secondary interactions also enhance the properties of covalently crosslinked hydrogels. A head-to-head comparison of PEG hydrogels crosslinked with tetrazine-norbornene and thiol-norbornene click chemistry reveals an approximately sixfold increase in storage modulus and unprecedented resistance to hydrolytic degradation in tetrazine click-crosslinked gels without substantial differences in gel fraction. Molecular dynamic simulations attribute these differences to the presence of secondary interactions between the tetrazine-norbornene cycloaddition products, which are absent in the thiol-norbornene crosslinked gels.
Asunto(s)
Materiales Biocompatibles , Hidrogeles , Química Clic , Polietilenglicoles , Compuestos de SulfhidriloRESUMEN
With the goal of generating anionic analogues to MN2 S2 â Mn(CO)3 Br we introduced metallodithiolate ligands, MN2 S22- prepared from the Cys-X-Cys biomimetic, ema4- ligand (ema=N,N'-ethylenebis(mercaptoacetamide); M=NiII , [VIV ≡O]2+ and FeIII ) to Mn(CO)5 Br. An unexpected, remarkably stable dimanganese product, (H2 N2 (CH2 C=O(µ-S))2 )[Mn(CO)3 ]2 resulted from loss of M originally residing in the N2 S24- pocket, replaced by protonation at the amido nitrogens, generating H2 ema2- . Accordingly, the ema ligand has switched its coordination mode from an N2 S24- cavity holding a single metal, to a binucleating H2 ema2- with bridging sulfurs and carboxamide oxygens within Mn-µ-S-CH2 -C-O, 5-membered rings. In situ metal-templating by zinc ions gives quantitative yields of the Mn2 product. By computational studies we compared the conformations of "linear" ema4- to ema4- frozen in the "tight-loop" around single metals, and to the "looser" fold possible for H2 ema2- that is the optimal arrangement for binucleation. XRD molecular structures show extensive H-bonding at the amido-nitrogen protons in the solid state.
RESUMEN
An active segment of the research community designing small molecules ("minimalist mimics" of peptide fragments) to interfere with protein-protein interactions have based their studies on an implicit hypothesis. Here we refer to this as the Secondary Structure Hypothesis, that might be defined as, "If a small molecule can orient amino acid side-chains in directions that resemble side-chains of the parent secondary structure at the interface, then that small molecule is a candidate to perturb the protein-protein interaction". Rigorous tests of this hypothesis require co-crystallization of minimalist mimics with protein receptors, and comparison of the bound conformations with the interface secondary structures they were designed to resemble. Unfortunately, to the best of our knowledge, there is no such analysis in the literature, and it is unlikely that enough examples will emerge in the near future to test the hypothesis. Research described here was designed to challenge this hypothesis from a different perspective. In a previous study, preferred conformations of a series of novel minimalist mimics were simulated then systematically overlaid on >240 000 crystallographically characterized protein-protein interfaces. Select data from that overlay procedure revealed chemotypes that overlay side chains on various PPI interfaces with a relatively high frequency of occurrence. The first aim of this work was to determine if good secondary structure mimics overlay frequently on PPI interfaces. The second aim of this work was to determine if overlays of preferred conformers at interface regions involve secondary structures. Thus situations where these conformations overlaid extremely well on PPI interfaces were analyzed to determine if secondary structures featured the PPI regions where these molecules overlaid in the previous study. Combining conclusions from these two studies enabled us to formulate a hypothesis that is complementary to the Secondary Structure Hypothesis, but, unlike this, is supported by abundant data. We call this the Interface Mimicry Hypothesis.
Asunto(s)
Modelos Químicos , Imitación Molecular , Proteínas/química , Modelos Moleculares , Unión Proteica , Estructura Secundaria de ProteínaRESUMEN
Small molecules that can interrupt or inhibit protein-protein interactions (PPIs) are valuable as probes in chemical biology and medicinal chemistry, but they are also notoriously difficult to develop. Design of non-peptidic small molecules that mimic amino acid side-chain interactions in PPIs ("minimalist mimics") is seen as a way to fast track discovery of PPI inhibitors. However, there has been little comment on general design criteria for minimalist mimics, even though such guidelines could steer construction of libraries to screen against multiple PPI targets. We hypothesized insight into general design criteria for minimalist mimics could be gained by comparing preferred conformations of typical minimalist mimic designs against side-chain orientations on a huge number of PPI interfaces. That thought led to this work which features nine minimalist mimic designs: one from the literature, and eight new "hypothetical" ones conceived by us. Simulated preferred conformers of these were systematically aligned with >240 000 PPI interfaces from the Protein Data Bank. Conclusions from those analyses did indeed reveal various design considerations that are discussed here. Surprisingly, this study also showed one of the minimalist mimic designs aligned on PPI interface segments more than 15 times more frequently than any other in the series (according to uniform standards described herein); reasons for this are also discussed.
Asunto(s)
Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , ARN Polimerasas Dirigidas por ADN/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Quinasa 2 Dependiente de la Ciclina/química , Quinasa 2 Dependiente de la Ciclina/metabolismo , ARN Polimerasas Dirigidas por ADN/química , ARN Polimerasas Dirigidas por ADN/metabolismo , Bases de Datos de Proteínas , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Simulación de Dinámica Molecular , Estructura Molecular , Unión Proteica/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , EstereoisomerismoRESUMEN
A high-valent, rhenium(V) oxo complex (PCP)ReOCl2 (1; PCP=bis(2,6-di-tert-butylphosphinomethyl)phenyl) undergoes a deprotonation and "dearomatization" upon treatment with LiN(SiMe3 )2 to give (P*CP)ReOCl (2 a), in which Re is bound to a new dianionic P*CP ligand. Compound 2 a was studied spectroscopically, structurally, and computationally and was determined to have non-negligible Re=C multiple bond character, leading to its formulation as a new pseudo-carbenoid species. Reaction of 2 a or its iodo analogue (P*CP)ReOI (2 b) with CO2 provided access to (PCP)ReOX(CO2 ) (X=Cl or I, 3 a/b), the product of 1,3-cycloaddition and C-C bond formation.
RESUMEN
Linearly arranged metal atoms that are embedded in discrete molecules have fascinated scientists across various disciplines for decades; this is attributed to their potential use in microelectronic devices on a submicroscopic scale. Luminescent oligonuclear Groupâ 11 metal complexes are of particular interest for applications in molecular light-emitting devices. Herein, we describe the synthesis and characterization of a rare, homoleptic, and neutral linearly arranged tetranuclear Cu(I) complex that is helically bent, thus representing a molecular coil in the solid state. This tetracuprous arrangement dimerizes into a unique octanuclear assembly bearing a linear array of six Cu(I) centers with two additional bridging cuprous ions that constitute a central pseudo-rhombic Cu(I) 4 cluster. The crystal structure determinations of both complexes reveal close d(10) â â â d(10) contacts between all cuprous ions that are adjacent to each other. The dynamic behavior in solution, DFT calculations, and the luminescence properties of these remarkable complexes are also discussed.
RESUMEN
The effects of charge states, charge sites and side chain interactions on conformational preferences of gas-phase peptide ions are examined by ion mobility-mass spectrometry (IM-MS) and molecular dynamics (MD) simulations. Collision cross sections (CCS) of [M + 2H](2+) and [M + 3H](3+) ions for a series of model peptides, viz. Ac-(AAKAA)nY-NH2 (AKn, n = 3-5) and Ac-Y(AEAAKA)nF-NH2 (AEKn, n = 2-5) are measured by using IM-MS and compared with calculated CCS for candidate ions generated by MD simulations. The results show that charge states, charge sites and intramolecular charge solvation are important determinants of conformer preference for AKn and AEKn ions. For AKn ions, there is a strong preference for helical conformations near the N-terminus and charge-solvated conformations near the C-terminus. For [AEKn + 2H](2+) ions, conformer preferences appear to be driven by charge solvation, whereas [AEKn + 3H](3+) ions favor more extended coil-type conformations.
Asunto(s)
Péptidos/química , Secuencia de Aminoácidos , Electrones , Simulación de Dinámica Molecular , Datos de Secuencia Molecular , Conformación Proteica , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
AIM: This study aimed to understand the interaction between interpersonal respect, diversity climate, mission fulfilment and engagement to better predict turnover in health care. BACKGROUND: Registered nurse turnover has averaged 14% and current nursing shortages are expected to spread. Few studies have studied employee engagement as a mediator between organisational context and turnover. METHOD: Study participants were employees working within 185 departments across ten hospitals within a large healthcare organisation in the USA. Although a total of 5443 employees work in these departments, employee opinion survey responses were aggregated by department before being linked to turnover rates gathered from company records. RESULT: Engagement fully mediated the relationship between respect and turnover and the relationship between mission fulfilment and turnover. Diversity climate was not related to turnover. CONCLUSION: Turnover in health care poses a significant threat to the mission of creating a healing environment for patients and these results demonstrate that workplace respect and connection to the mission affect turnover by decreasing engagement. IMPLICATIONS FOR NURSING MANAGEMENT: The findings demonstrated that to increase engagement, and improve turnover rates in health care, it would be beneficial for organisations, and nurse management to focus on improving mission fulfilment and interpersonal relationships.
Asunto(s)
Relaciones Interprofesionales , Satisfacción en el Trabajo , Enfermeras Administradoras/normas , Cultura Organizacional , Reorganización del Personal/estadística & datos numéricos , Adulto , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Polynuclear transition metal complexes, which frequently constitute the active sites of both biological and chemical catalysts, provide access to unique chemical transformations that are derived from metal-metal cooperation. Reductive elimination via ligand-bridged binuclear intermediates from bimetallic cores is one mechanism by which metals may cooperate during catalysis. We have established families of Rh2 complexes that participate in HX-splitting photocatalysis in which metal-metal cooperation is credited with the ability to achieve multielectron photochemical reactions in preference to single-electron transformations. Nanosecond-resolved transient absorption spectroscopy, steady-state photocrystallography, and computational modeling have allowed direct observation and characterization of Cl-bridged intermediates (intramolecular analogues of classical ligand-bridged intermediates in binuclear eliminations) in halogen elimination reactions. On the basis of these observations, a new class of Rh2 complexes, supported by CO ligands, has been prepared, allowing for the isolation and independent characterization of the proposed halide-bridged intermediates. Direct observation of halide-bridged structures establishes binuclear reductive elimination as a viable mechanism for photogenerating energetic bonds.
Asunto(s)
Halógenos/química , Compuestos Organometálicos/química , Procesos Fotoquímicos , Rodio/química , Catálisis , Cristalización , Modelos Moleculares , Conformación Molecular , Teoría CuánticaRESUMEN
Minimalist secondary structure mimics are typically made to resemble one interface in a protein-protein interaction (PPI), and thus perturb it. We recently proposed suitable chemotypes can be matched with interface regions directly, without regard for secondary structures. Here we describe a modular synthesis of a new chemotype 1, simulation of its solution-state conformational ensemble, and correlation of that with ideal secondary structures and real interface regions in PPIs. Scaffold 1 presents amino acid side-chains that are quite separated from each other, in orientations that closely resemble ideal sheet or helical structures, similar non-ideal structures at PPI interfaces, and regions of other PPI interfaces where the mimic conformation does not resemble any secondary structure. 68 different PPIs where conformations of 1 matched well were identified. A new method is also presented to determine the relevance of a minimalist mimic crystal structure to its solution conformations. Thus DLD-1 faf crystallized in a conformation that is estimated to be 0.91â kcal mol(-1) above the minimum energy solution state.
Asunto(s)
Piperidinas/química , Estructura Secundaria de Proteína/fisiología , Aminoácidos , Modelos Moleculares , Conformación Molecular , Unión ProteicaRESUMEN
Small molecule probes that selectively perturb protein-protein interactions (PPIs) are pivotal to biomedical science, but their discovery is challenging. We hypothesized that conformational resemblance of semirigid scaffolds expressing amino acid side-chains to PPI-interface regions could guide this process. Consequently, a data mining algorithm was developed to sample huge numbers of PPIs to find ones that match preferred conformers of a selected semirigid scaffold. Conformations of one such chemotype (1aaa; all methyl side-chains) matched several biomedically significant PPIs, including the dimerization interface of HIV-1 protease. On the basis of these observations, four molecules 1 with side-chains corresponding to the matching HIV-1 dimerization interface regions were prepared; all four inhibited HIV-1 protease via perturbation of dimerization. These data indicate this approach may inspire design of small molecule interface probes to perturb PPIs.
Asunto(s)
Colorantes Fluorescentes/farmacología , Proteasa del VIH/química , Bibliotecas de Moléculas Pequeñas/farmacología , Algoritmos , Dimerización , Colorantes Fluorescentes/química , Proteasa del VIH/metabolismo , Modelos Moleculares , Unión Proteica/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-ActividadRESUMEN
Oligo-pyrrolinone-pyrrolidines (generic structure 1) have the potential to interfere with protein-protein interactions (PPIs), but to reduce this to practice it is necessary to be able to synthesize these structures with a variety of different side chains corresponding to genetically encoded proteins. This paper describes expansion of the synthetic scope of 1, the difficulties encountered in this process, particularly issues with epimerization and slow coupling rates, and methods to overcome them. Finally, spectroscopic and physicochemical properties as well as proteolytic stabilities of molecules in this series were measured; these data highlight the suitability of oligo-pyrrolinone-pyrrolidines for the development of pharmacological probes or pharmaceutical leads.
Asunto(s)
Proteínas/química , Pirrolidinas/química , Células CACO-2 , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Estructura Molecular , Unión Proteica , Pirrolidinas/síntesis químicaRESUMEN
Peptide mimics that display amino acid side-chains on semi-rigid scaffolds (not peptide polyamides) can be referred to as minimalist mimics. Accessible conformations of these scaffolds may overlay with secondary structures giving, for example, "minimalist helical mimics". It is difficult for researchers who want to apply minimalist mimics to decide which one to use because there is no widely accepted protocol for calibrating how closely these compounds mimic secondary structures. Moreover, it is also difficult for potential practitioners to evaluate which ideal minimalist helical mimics are preferred for a particular set of side-chains. For instance, what mimic presents i, i + 4, i + 7 side-chains in orientations that best resemble an ideal α-helix, and is a different mimic required for a i, i + 3, i + 7 helical combination? This article describes a protocol for fitting each member of an array of accessible scaffold conformations on secondary structures. The protocol involves: (i) use quenched molecular dynamics (QMD) to generate an ensemble consisting of hundreds of accessible, low energy conformers of the mimics; (ii) representation of each of these as a set of Cα and Cß coordinates corresponding to three amino acid side-chains displayed by the scaffolds; (iii) similar representation of each combination of three side-chains in each ideal secondary structure as a set of Cα and Cß coordinates corresponding to three amino acid side-chains displayed by the scaffolds; and, (iv) overlay Cα and Cß coordinates of all the conformers on all the sets of side-chain "triads" in the ideal secondary structures and express the goodness of fit in terms of root mean squared deviation (RMSD, Å) for each overlay. We refer to this process as Exploring Key Orientations on Secondary structures (EKOS). Application of this procedure reveals the relative bias of a scaffold to overlay on different secondary structures, the "side-chain correspondences" (e.g. i, i + 4, i + 7 or i, i + 3, i + 4) of those overlays, and the energy of this state relative to the minimum located. This protocol was tested on some of the most widely cited minimalist α-helical mimics (1-8 in the text). The data obtained indicates several of these compounds preferentially exist in conformations that resemble other secondary structures as well as α-helices, and many of the α-helical conformations have unexpected side-chain correspondences. These observations imply the featured minimalist mimics have more scope for disrupting PPI interfaces than previously anticipated. Finally, the same simulation method was used to match preferred conformations of minimalist mimics with actual protein/peptide structures at interfaces providing quantitative comparisons of predicted fits of the test mimics at protein-protein interaction sites.
Asunto(s)
Imitación Molecular , Estructura Secundaria de ProteínaRESUMEN
We present herein a framework for measuring the internal energy distributions of vibrationally excited molecular ions emitted from hypervelocity nanoprojectile impacts on organic surfaces. The experimental portion of this framework is based on the measurement of lifetime distributions of "thermometer" benzylpyridinium ions dissociated within a time of flight mass spectrometer. The theoretical component comprises re-evaluation of the fragmentation energetics of benzylpyridinium ions at the coupled-cluster singles and doubles with perturbative triples level. Vibrational frequencies for the ground and transition states of select molecules are reported, allowing for a full description of vibrational excitations of these molecules via Rice-Ramsperger-Kassel-Marcus unimolecular fragmentation theory. Ultimately, this approach is used to evaluate the internal energy distributions from the measured lifetime distributions. The average internal energies of benzylpyridinium ions measured from 440 keV Au400(+4) impacts are found to be relatively low (~0.24 eV/atom) when compared with keV atomic bombardment of surfaces (1-2 eV/atom).
Asunto(s)
Nanopartículas/química , Compuestos de Piridinio/química , Termodinámica , Iones/química , Simulación de Dinámica Molecular , Estructura Molecular , Propiedades de Superficie , VibraciónRESUMEN
As fused filament fabrication (FFF) continues to gain popularity, many studies are turning to nanomaterials or optimization of printing parameters to improve the materials' properties; however, many overlook how materials formulation and additive manufacturing (AM) processes cooperatively engineer the evolution of properties across length scales. Evaluating the in-process evolution of the nanocomposite using AM will provide a fundamental understanding of the material's microstructure, which can be tailored to create unique characteristics in functionality and performance. In this study, the crystallinity behavior of polyetheretherketone (PEEK) was studied in the presence of carbon nanotubes (CNTs) as a nucleation aid for improved crystallization during FFF processing. Using various characterization techniques and molecular dynamics simulations, it was discovered that the crystallization behavior of extruded filaments is very different from that of 3D printed roads. Additionally, the printed material exhibited cold crystallization, and the CNT addition increased the crystallization of printed roads, which were amorphous without CNT addition. Tensile strength and modulus were increased by as much as 42 and 51%, respectively, due to higher crystallinity during printing. Detailed knowledge on the morphology of PEEK-CNT used in FFF allows gaining a fundamental understanding of the morphological evolution occurring during the AM process that in turn enables formulating materials for the AM process to achieve tailored mechanical and functional properties, such as crystallinity or conductivity.
RESUMEN
Despite being a pillar of high-performance materials in industry, manufacturing carbon fiber composites with simultaneously enhanced multifunctionality and structural properties has remained elusive due to the lack of practical bottom-up approaches with control over nanoscale interactions. Guided by the droplet's internal currents and amphiphilicity of nanomaterials, herein, a programmable spray coating is introduced for the deposition of multiple nanomaterials with tailorable patterns in composite. It is shown that such patterns regulate the formation of interfaces, damage containment, and electrical-thermal conductivity of the composites, which is absent in conventional manufacturing that primarily rely on incorporating nanomaterials to achieve specific functionalities. Molecular dynamics simulations show that increasing the hydrophilicity of the hybrid nanomaterials, which is synchronous with shifting patterns from disk to ring, improves the interactions between the carbon surfaces and epoxy at the interfaces,manifested in enhanced interlaminar and flexural performance. Transitioning from ring to disk creates a larger interconnected network leading to improved thermal and electrical properties without penalty in mechanical properties. This novel approach introduces a new design , where the mechanical and multifunctional performance is controlled by the shape of the deposited patterns, thus eliminating the trade-off between properties that are considered paradoxical in today's manufacturing of hierarchical composites.
RESUMEN
The ZnCl(2)-mediated tandem Mukaiyama aldol lactonization (TMAL) reaction of aldehydes and thiopyridyl ketene acetals provides a versatile, highly diastereoselective approach to trans-1,2-disubstituted ß-lactones. Mechanistic and theoretical studies described herein demonstrate that both the efficiency of this process and the high diastereoselectivity are highly dependent upon the type of ketene acetal employed but independent of ketene acetal geometry. Significantly, we propose a novel and distinct mechanistic pathway for the ZnCl(2)-mediated TMAL process versus other Mukaiyama aldol reactions based on our experimental evidence to date and further supported by calculations (B3LYP/BSI). Contrary to the commonly invoked mechanistic extremes of [2+2] cycloaddition and aldol lactonization mechanisms, investigations of the TMAL process suggest a concerted but asynchronous transition state between aldehydes and thiopyridyl ketene acetals. These calculations support a boat-like transition state that differs from commonly invoked Mukaiyama "open" or Zimmerman-Traxler "chair-like" transition-state models. Furthermore, experimental studies support the beneficial effect of pre-coordination between ZnCl(2) and thiopyridyl ketene acetals prior to aldehyde addition for optimal reaction rates. Our previously proposed, silylated ß-lactone intermediate that led to successful TMAL-based cascade sequences is also supported by the described calculations and ancillary experiments. These findings suggested that a similar TMAL process leading to ß-lactones would be possible with an oxopyridyl ketene acetal, and this was confirmed experimentally, leading to a novel TMAL process that proceeds with efficiency comparable to that of the thiopyridyl system.
RESUMEN
The electronic structures of two uranium compounds supported by redox-active α-diimine ligands, ((Mes)DAB(Me))(2)U(THF) (1) and Cp(2)U((Mes)DAB(Me)) (2) ((Mes)DAB(Me) = [ArNâC(Me)C(Me)âNAr]; Ar = 2,4,6-trimethylphenyl (Mes)), have been investigated using both density functional theory and multiconfigurational self-consistent field methods. Results from these studies have established that both uranium centers are tetravalent, that the ligands are reduced by two electrons, and that the ground states of these molecules are triplets. Energetically low-lying singlet states are accessible, and some transitions to these states are visible in the electronic absorption spectrum.
RESUMEN
Pharmacophore modeling is an important step in computer-aided drug design for identifying interaction points between the receptor and ligand complex. Pharmacophore-based models can be used for de novo drug design, lead identification, and optimization in virtual screening as well as for multi-target drug design. There is a need to develop a user-friendly interface to filter the pharmacophore points resulting from multiple ligand conformations. Here, we present ELIXIR-A, a Python-based pharmacophore refinement tool, to help refine the pharmacophores between multiple ligands from multiple receptors. Furthermore, the output can be easily used in virtual pharmacophore-based screening platforms, thereby contributing to the development of drug discovery.