Development of a proteochemometric-based support vector machine model for predicting bioactive molecules of tubulin receptors

Molecular Diversity - Microtubules are receiving enormous interest in drug discovery due to the important roles they play in cellular functions. Targeting tubulin polymerization presents an...     

The Great Myths of Polymer Melt Rheology,Part I: Comparison of Experiment and Current Theory

Abstract

Star polymers consisting of poly(?‐caprolactone), (PCL), grafted onto third generation dendrimer, which had hyperbranched and dendron cores, were studied by polarized light microscopy together with reference linear PCL. The degree of polymerization of the PCL arms in the star polymers ranged between 14 and 81. The star polymers exhibited a greater tendency than the linear polymers to form spherulites. It is suggested that the preference of the star polymers for forming spherulites is due to the presence of amorphous material—dendritic cores and PCL cilia—between crystal lamellae that generates the necessary pressure to force the lamellae to diverge at lamellar branch points. The linear growth rate data followed a single crystallization regime. The fold surface free energy was higher for the star polymers than for their linear analogs. It is proposed that the presence of the large and rigid dendritic cores on the fold surfaces of the star polymer crystals increases the fold surface energy.     

Investigation of the structural and dynamic basis of kinesin dissociation from microtubule by atomistic molecular dynamics simulations

Kinesin is a molecular motor that can step processively on microtubules via the hydrolysis of ATP molecules. An important factor characterizing the processivity of the kinesin motor is its dissociation from the microtubule. Here, using all-atom molecular dynamics simulations, we studied the dissociation process of the kinesin head in weak-microtubule-binding or ADP state from tubulin on the basis of the available high-resolution structural data for the head and tubulin. By analyzing the simulated snapshots of the structure of the head-tubulin complex we provided detailed structural and dynamic information for the dissociation process. We found that the dissociation of the head along different directions relative to the tubulin exhibits very different dynamic behaviors. Moreover, the potential forms or energy landscapes of the interaction between the head and tubulin along different directions were determined. The studies have important implications for the detailed molecular mechanism of the dissociation of the kinesin motor and thus are critical to the mechanism of its processivity.     

The influence of macromolecular polymerization of spin-lattice relaxation of aqueous solutions

The docking or polymerization of globular proteins is demonstrated to cause changes in proton NMR spin-lattice (T1) relaxation times. Studies on solutions of lysozyme, bovine serum albumin, actin, and tubulin are used to demonstrate that two mechanisms account for the observed changes in T1. Polymerization displaces the hydration water sheath surrounding globular proteins in solution that causes an increase in T1. Polymerization also slows the average tumbling rate of the proteins, which typically causes a contrary decrease in T1. The crystallization reaction of lysozyme in sodium chloride solution further demonstrates that the "effective" molecular weight can either decrease or increase T1 depending on how much the protein is slowed. The displacement of hydration water increases T1 because it speeds up the mean motional state of water in the solution. Macromolecular docking typically decreases T1 because it slows the mean motional state of the solute molecules. Cross-relaxation between the proteins and bound water provides the mechanism that allows macromolecular motion to influence the relaxation rate of the solvent. Fast chemical exchange between bound, structured, and bulk water accounts for monoexponential spin-lattice relaxation. Thus the spin-lattice relaxation rate of water in protein solutions is a complex reflection of the motional properties of all the molecules present containing proton magnetic dipoles. It is expected, as a result, that the characteristic relaxation times of tissues will reflect the influence of polymerization changes related to cellular activities.     

The (p,n) reaction on cadmium isotopes leading to the ground- and excited-state analogs

The (p, n) reactions to ground- and excited-state analogs on ^110,114,116Cd have been studied at a bombarding energy of 25 MeV. Angular distributions of emitted neutrons leading to ground-state analogs, and 2⁺, 3^? and 4⁺ excited-state analogs were obtained for each target. Angular distributions of differential cross sections to the ground-state analog agree with the predictions obtained from macroscopic DWBA calculations in which a Lane potential is employed. Coupled-channel calculations indicate the importance of two-step processes in the (p, n) transition to an excited-state analog. Further, the calculation using a larger value for the deformation parameter of the isovector part than of the isoscalar one fairly well describes the 2⁺ excited-state analog.     

Development of fluorinated,NMR-active spin traps for studies of free radical chemistry

Five fluorinated analogs of the spin trap phenyl-t-butyl nitrone (PBN) have been synthesized and evaluated for use as NMR-active traps. The introduction of the fluorine substituent allows selective observation of chemical reactions involving the spin traps. Although the paramagnetic adducts themselves are not directly observable by this approach as a consequence of extensive broadening, the reduced forms (hydroxylamines) can be readily observed. NMR studies of the trapping of the phenyl radical produced from the thermal decomposition of phenylazotriphenyl methane have been carried out. The observation of fluorinated benzaldehydes in these studies reflects the formation and subsequent degradation of oxygen-centered radicals under some conditions. Relative trapping efficiencies for the phenyl radical in the series 2-F, 4-F, 2,6-difluoro, 2-CF₃, and 4-CF₃ substituted PBN analogs have been determined based on an analysis of the ¹⁹F NMR resonance intensities of the reduced phenyl radical adducts. The relatively large proton hyperfine coupling constants observed for 2,6-difluoro and 2-CF₃ PBN analogs allow direct observation by ESR of adduct formation in solutions containing both PBN and either of these analogs. The introduction of fluorine substituents into the trap has only a small effect on trapping efficiency.     

A coupled-cluster approach to the relative strains in [1.1.1]propellane,its derivatives and hetero[1.1.1]propellanes

The molecule [1.1.1]propellane and its neutral boron, nitrogen, oxygen, sulphur, S–O, and SO₂ analogs as well as the methyl, hexafluoro, and tri-carbonyl substituted derivatives have been investigated by theoretical calculations at the coupled-cluster singles and doubles level with an augmented polarized double zeta basis set. The geometries were optimized and vibrational analysis was carried out for each species. The main objective of this study was to determine the relative strain in these systems, which in turn is a predictor of stability and reactivity providing valuable information about potentially viable synthetic targets. The systems with the least strain are the nitrogen, boron and the S–O analogs, whereas the SO₂ substituted molecule and the hexafluoride and tricarbonyl substituted analogs exhibited the largest amount of strain. Geometrical features are also investigated and it is demonstrated that non-bonded repulsive interactions contribute significantly to the strain in some of the systems since cage-like structures force relatively short non-bonded distances.     

Eynard–Mehta Theorem, Schur Process, and their Pfaffian Analogs

We give simple linear algebraic proofs of the Eynard–Mehta theorem, the Okounkov-Reshetikhin formula for the correlation kernel of the Schur process, and Pfaffian analogs of these results. We also discuss certain general properties of the spaces of all determinantal and Pfaffian processes on a given finite set     

Hsp27 and axonal growth in adult sensory neurons <Emphasis Type="Italic">in vitro</Emphasis>

Background  

Neurite growth can be elicited by growth factors and interactions with extracellular matrix molecules like laminin. Among the targets of the signalling pathways activated by these stimuli are cytoskeletal elements, such as actin, tubulin and neurofilaments. The cytoskeleton can also be modulated by other proteins, such as the small heat shock protein Hsp27. Hsp27 interacts with actin and tubulin in non-neuronal cells and while it has been suggested to play a role in the response of some neurons to injury, there have been no direct studies of its contribution to axonal regeneration.     

POLYMERIZATION,MORPHOLOGY, AND CRYSTAL STRUCTURE OF POLY(p-BENZAMIDE)*

Isothermal polymerization of acetaminobenzoic acid at various temperatures in bulk and solution was monitored by acetic acid evolution. The polymerization took place initially in a homogeneous phase, but it soon changed to heterogeneous as the polymer precipitated from the melt or solution. The reaction course consisted of a short induction period, followed by a fast second-order reaction and a third slow, also second-order, reaction. The different polymerization rates in the second and third stage were due to polymer precipitation. The degree of polymerization of the resulting polymer was generally low, usually less than 5. The polymer was highly crystalline and prone to decarboxylation at temperatures above 300°C. Sample structure and morphology were characterized by various lamellar formations similar to those seen previously in many aromatic polyesters. Epitaxial solution polymerization/crystallization on mica resulted in three different morphologies, the most unique being shish kebab–type structures. Polybenzamide [poly(p-aminobenzoate)] is polymorphic; the most frequently seen hk0 electron diffraction patterns were similar to those from phase I of aromatic polyesters. Phase II of polybenzamide was seen only rarely. Simulation, using Cerius², suggested equal agreement with [001], [100], and fiber electron diffraction (ED) patterns and X-ray powder patterns for two different orthorhombic unit cells (a = 7.71, b = 5.35, c = 12.94 Å, ρ = 1.55 g/cm³); both have a parallel packing of adjacent molecules, but in one, successive phenyl rings along a given chain are parallel, while in the other they are twisted at ±30°. For both unit cells, neighboring molecules were displaced by ±0.14 Å along c to obtain better agreement with the observed patterns. The [010] patterns could distinguish between the two cells, but were not obtainable.

     

Molecular Modeling and Design of Arylthioindole Derivatives as Tubulin Inhibitors

对一系列具有抗人乳腺癌细胞系MCF-7生物活性的微管蛋白抑制剂─芳基硫代吲哚衍生物(arylthioindole),进行了三维定量构效关系(3D-QSAR)和对接(docking)研究. 在训练集中,建立了具有良好统计质量和预报能力的比较分子力场分析(CoMFA) 模型,其非交叉验证相关系数平方R₂为0.898,交叉验证相关系数平方q₂为0.654. 同时在测试集的验证中得到预测相关系数平方R₂(pred)为0.816, 进一步表明了该模型具有较高的预测能力. 此外,通过对接研究,获得了这些化合物与微管蛋白作用的键合方式和构象,发现该系列化合物的CoMFA力场分布与对接结合位点上的三维拓朴结构相一致. 根据CoMFA和对接分析的结果,细致地讨论和总结了有利于提高或改进该类化合物活性的主要因素,即在取代基R3、R4和R5上引进高电负性的基团,在取代基R6上引进带有高电负性且大体积的基团,以及在取代基R7上引进小体积的基团等都是有利的. 基于这些研究结果,在理论上还设计了5个新的具有较高活性的化合物.     

Polymerization rate and mechanism of ultrasonically initiated emulsion polymerization of n-butyl acrylate

The factors affecting the induction period and polymerization rate in ultrasonically initiated emulsion polymerization of n-butyl acrylate (BA) were investigated. The induction period takes only an instant in ultrasonically initiated emulsion polymerization of BA without any added initiator by enhancing the N2 flow rate. Increasing temperature, power output and SDS concentration, decreasing the monomer concentration results in further decreasing induction period and enhanced polymerization rate. Under optimized reaction conditions the conversion of BA reaches 92% in 11 min. The polymerization rate can be controlled by varying reaction parameters. The apparatus of ultrasonically initiated semi-continuous and continuous emulsion polymerization were set up and the feasibility was first studied. Based on the experimental results, a free radical polymerization mechanism for ultrasonically initiated emulsion polymerization was proposed, including the sources of the radicals, the process of radical formation, the locus of polymerization and the polymerization process. Compared with conventional emulsion polymerization, where the radicals come from thermal decomposition of a chemical initiator, ultrasonically initiated emulsion polymerization has attractive features such as no need for a chemical initiator, lower reaction temperature, faster polymerization rate, and higher molecular weight of the polymer prepared.     

Hydrodynamics of nanoscopic tubulin rings in dilute solutions

We combine fluorescence correlation spectroscopy and sedimentation velocity measurements to probe the hydrodynamic behavior of tubulin dimers and nanoscopic tubulin rings. The rings are rigid, have circular geometry, and are monodisperse in size. We use the high-precision ratio of the sedimentation coefficients and that of the translational diffusion coefficients to validate theories for calculating the hydrodynamic properties of supramolecular structures.     

Raman spectroscopic characterization of the copper,cobalt, and nickel selenites: Synthetic analogs of chalcomenite,cobaltomenite, and ahlfeldite

Raman spectroscopy has been used to study synthetic analogs of the minerals chalcomenite, cobaltomenite, and ahlfeldite occurring in nature. The results obtained are compared with the spectra of these minerals. In general, the majority of vibrational bands of synthetic species are in good agreement with natural chalcomenite, cobaltomenite, and ahlfeldite. The noticeable discrepancies are found for the bands assigned to the deformation mode of selenite groups. A better signal-to-noise ratio realized with synthetic species aids in comprehensive analysis of the spectra, especially in the region of water bands.     

Graphite,Graphene, and the Flat Band Superconductivity

Superconductivity has been observed in bilayer graphene [1, 2]. The main factor that determines the mechanism of the formation of this superconductivity is the “magic angle” of twist of two graphene layers, at which the electronic band structure becomes nearly flat. The specific role played by twist and by the band flattening has been earlier suggested for explanations of the signatures of room-temperature superconductivity observed in the highly oriented pyrolytic graphite (HOPG), when the quasi two-dimensional interfaces between the twisted domains are present. The interface contains the periodic array of misfit dislocations (analogs of the boundaries of the unit cell of the Moiré superlattice in bilayer graphene), which provide the possible source of the flat band. This demonstrates that it is high time for combination of the theoretical and experimental efforts in order to reach the reproducible room-temperature superconductivity in graphite or in similar real or artificial materials.     

Natural Abudance 17O NMR Studies of Thiol Esters and Related Analogs

Natural abundance ¹⁷O NMR data for a series of thiol esters and related analogs are reported. The carbonyl signal of the thiol esters range from 463 ppm to 514 ppm; these values are downfield of their oxygen analogs by ca. 150 ppm. A linear relationship between the ¹⁷O NMR chemical shift of the thio-compounds and their oxo-analogs is observed.     

The Van Vleck formula,Maslov theory,and phase space geometry

The Van Vleck formula is an approximate, semiclassical expression for the quantum propagator. It is the starting point for the derivation of the Gutzwiller trace formula, and through this, a variety of other expansions representing eigenvalues, wave functions, and matrix elements in terms of classical periodic orbits. These are currently among the best and most promising theoretical tools for understanding the asymptotic behavior of quantum systems whose classical analogs are chaotic. Nevertheless, there are currently several questions remaining about the meaning and validity of the Van Vleck formula, such as those involving its behavior for long times. This article surveys an important aspect of the Van Vleck formula, namely, the relationship between it and phase space geometry, as revealed by Maslov's theory of wave asymptotics. The geometrical constructions involved are developed with a minimum of mathematical formalism.     

Poly(N-methylaniline)/Montmorillonite Composite: Chemical Synthesis,Characterization, and Application in Water Treatment

Poly(N-methylaniline)/montmorillonite (PNMA/MMT) composite particles were obtained by using a simple in situ chemical oxidative polymerization method in hydrochloric acid solutions. Fourier transform infrared (FTIR) spectra, UV-visible absorption spectra and scanning electron microscopy (SEM) were carried out to characterize the as-prepared PNMA/MMT composite. On the basis of spectroscopy and morphology analysis, the probable polymerization mechanism was proposed. The potential application of PNMA/MMT composite for removal of heavy metal ions, such as Cu²⁺ and Zn²⁺, in aqueous solution was also investigated.     

Novel antimitotic agents related to tubuloclustin: synthesis and biological evaluation

Tubuloclustin [N-(7-adamant-2-yloxy-7-oxoheptanoyl)-N-deacetylcolchicine], a highly cytotoxic anti-tubulin compound is known for its ability to promote microtubule disassembly followed by the formation of tubulin clusters of unique morphology. Three series of antimitotic agents related to tubuloclustin were designed and synthesized in order to enhance the molecular diversity of “tubuloclustin-like” family of compounds. The series of compounds with modified adamantane moiety was highly potent in cytotoxic effect on human lung carcinoma A549 cells (EC50 = 6–400 nM) and was active in affecting the microtubule arrays and induction of strong tubulin clusterization. In two other sets of compounds, the colchicine moiety of tubuloclustin was replaced by podophyllotoxin or combretastatin A-4. All combretastatin A-4 derivatives displayed noticeable cytotoxic activity (\(\hbox {EC}50=0.8{-}1.6\,\upmu \hbox {M}\)) but their effect on microtubules depended on the position of the linker attachment. Podophyllotoxin derivatives were also toxic to A549 cells (\(\hbox {EC}50=0.38{-}0.50\,\upmu \hbox {M}\)) and caused both microtubule depolymerization and some tubulin clustering. The data obtained gave additional evidence that the whole panel of C7-colchicine, podophyllotoxin and combretastatin derivatives could manifest clustering effect, and the strength of this effect correlated with cytotoxic activity of the compounds.     

Nonlinear ionic pulses along microtubules

Microtubules are cylindrically shaped cytoskeletal biopolymers that are essential for cell motility, cell division and intracellular trafficking. Here, we investigate their polyelectrolyte character that plays a very important role in ionic transport throughout the intra-cellular environment. The model we propose demonstrates an essentially nonlinear behavior of ionic currents which are guided by microtubules. These features are primarily due to the dynamics of tubulin C-terminal tails which are extended out of the surface of the microtubule cylinder. We also demonstrate that the origin of nonlinearity stems from the nonlinear capacitance of each tubulin dimer. This brings about conditions required for the creation and propagation of solitonic ionic waves along the microtubule axis. We conclude that a microtubule plays the role of a biological nonlinear transmission line for ionic currents. These currents might be of particular significance in cell division and possibly also in cognitive processes taking place in nerve cells.