Molecular Dynamics Simulations of Neat Vinyl Ester and Vapor-Grown Carbon Nanofiber/Vinyl Ester Resin Composites

Molecular dynamics (MD) simulations have been performed to investigate the system equilibrium through the atomic/molecular interactions of a liquid vinyl ester (VE) thermoset resin with the idealized surfaces of both pristine vapor-grown carbon nanofibers (VGCNFs) and oxidized VGCNFs. The VE resin has a mole ratio of styrene to bisphenol-A-diglycidyl dimethacrylate VE monomers consistent with a commercially available 33 wt% styrene VE resin (Derakane 441-400). The VGCNF-VE resin interactions may influence the distribution of the liquid VE monomers in the system and the formation of an interphase region. Such an interphase may possess a different mole ratio of VE resin monomers at the vicinity of the VGCNF surfaces compared to the rest of the system after resin curing. Bulk nano-reinforced material properties are highly dependent on the interphase features because of the high surface area to volume ratio of nano-reinforcements. For example, higher length scale micromechanical calculations suggest that the volume fraction and properties of the interphase can have a profound effect on bulk material properties. Interphase formation, microstructure, geometries, and properties in VGCNF-reinforced polymeric composites have not been well characterized experimentally, largely due to the small size of typical nano-reinforcements and interphases. Therefore, MD simulations offer an alternative means to probe the nano-sized formation of the interphase and to determine its properties, without having to perform fine-scale experiments. A robust crosslinking algorithm for VE resin was then developed as a key element of this research. VE resins are crosslinked via free radical copolymerization account for regioselectivity and monomer reactivity ratios. After the VE crosslinked network was created, the constitutive properties of the resin were calculated. This algorithm will be used to crosslink equilibrated VE resin systems containing both pristine and oxidized VGCNFs. An understanding of formation and kinematics of a crosslinked network obtained via MD simulations can facilitate nanomaterials design and can reduce the amount of nanocomposite experiments required. VGCNF pull-out simulations will then be performed to determine the interfacial shear strength between VGCNFs and the matrix. Interphase formation, thickness and interfacial shear strength can directly feed into higher length scale micromechanical models within a global multiscale analysis framework

Polymeric-based membranes for hydrogen enrichment and natural gas sweetening

Ph.DDOCTOR OF PHILOSOPH

Controlled nanostructure and high loading of single-walled carbon nanotubes reinforced polycarbonate composite

Abstract This paper presents an effective technique to fabricate thermoplastic nanocomposites with high loading of well-dispersed single-walled carbon nanotubes (SWNTs). SWNT membranes were made from a multi-step dispersion and filtration method, and then impregnated with polycarbonate solution to make thermoplastic nanocomposites. High loading of nanotubes was achieved by controlling the viscosity of polycarbonate solution. SEM and AFM characterization results revealed the controlled nanostructure in the resultant nanocomposites. Dynamic mechanical property tests indicated that the storage modulus of the resulting nanocomposites at 20 wt% nanotubes loading was improved by a factor of 3.4 compared with neat polycarbonate material. These results suggest the developed approach is an effective way to fabricate thermoplastic nanocomposites with good dispersion and high SWNT loading

An Assessment Of Forcite Approaches In Predictiing Young’s Modulus From Crystal Structure

University of Minnesota M.S. thesis. July 2019. Major: Pharmaceutics. Advisor: Changquan Sun. 1 computer file (PDF); vii, 52 pages.Improving the efficiency of tablet manufacturing in pharmaceutical industry has always attracted great concern. The mechanical properties of drugs are important for successful tablet production Thus, the knowledge of mechanical properties of pharmaceutical compound in pre-formulation stage facilitates tablet formulation development. A fast and accurate computational method for predicting crystal mechanical properties from crystal structure is extremely valuable since the availability of pharmaceutical active ingredients (APIs) is usually very limited. Methods based on the potential surface energy simulation are fast but their accuracy has not been systematically evaluated using a large set of crystals. The goal of the current study was to evaluate accuracy of predicted Young’s modulus (E) using the Forcite module in commercial software, Material Studio. The predicted E values of 50 organic crystals were compared to experimental values obtained by nanoindentation to assess their accuracy. A method to predict the E values on specific crystal faces was established to improve correlation by accounting for anisotropy of crystal mechanical properties. The correlation with experimental values remained poor. Detailed analyses of calculated E map of three crystals still failed to produce accurate E. Thus, the current Forcite module in Materials Studio for routine crystal form screening should be used with caution

Automated protein NMR data analysis and its application to a-synuclein fibrils

In principle, nuclear magnetic resonance (NMR) spectroscopy provides structural and conformational information with sub-Angstrom precision and the ability to measure dynamics with timescales ranging from femtoseconds to years, all with atomic specificity. However, due to the relatively low sensitivity of NMR, fundamental limits on spectral resolution, and the complexity of the quantum mechanical phenomena NMR exploits, that wealth of information often remains out of reach. The highly varied presentation of molecular information in NMR spectra and the difficulty of numerical simulation of non-trivial systems has lead the majority of data analysis to be performed by trained experts, and because of its time-intensive nature, that analysis is rarely replicated by a third party or validated in an objective manner. In this dissertation I report my efforts to automate NMR data analysis in an objective and replicable manner and to provide tools for validation of resulting three-dimensional structures by direct comparison to raw spectral data. The first method, COMPASS, attempts to extract as much information as possible from a single 13C-13C two-dimensional spectrum for the determination of protein structure and successfully identified the true structure of 15 test proteins. The second method, GPS, predicts features of data that would be expected given a set of chemical shift assignments and possibly a three-dimensional structure and uses the presence or absence of those features in experimental spectra to refine or validate a given structure. I then report my application of these computational methods to the problems of refining an a-synuclein fibril structure with proton-detected NMR data, the analysis and characterization of a pair of interrelated a-synuclein fibril strains with distinct pathological properties, and to the general question of fibril polymorphism, a phenomenon that presents a substantial challenge to forming consistent conclusions about fibril properties and interactions across samples and research groups

The Migration of Plasticisers and Interaction of Nitrogen Dioxide and Water in Nitrocellulose Binder Systems

A nitrocellulose binder holds the explosive ingredients together in a polymer bonded explosive or propellant. The binder dissipates energy from hazardous stimuli with the aim of producing a less sensitive explosive. To improve the overall mechanical properties of a binder a plasticiser is added, however plasticiser migration from the binder polymer matrix deteriorates the mechanical properties and reduces the service life of the energetic material. To assess the migration of the plasticisers 2,4-dinitroethylbenzene, 2,4,6-trinitroethylbenzene and 1-nitramino-2,3-dinitroxypropane from each of the nitrocellulose binders, diffusion coefficients and activation energies of diffusion were obtained for each plasticiser molecule via molecular dynamics simulation. The two nitrocellulose binder systems also underwent molecular dynamics simulations to investigate the interaction of water and nitrogen dioxide in each system. Reaction of nitrogen dioxide with water produces nitric acid which is thought to further react and degrade the nitrocellulose. Plasticiser migration was found to be faster in a nitrocellulose binder plasticised with 2,4-dinitroethylbenzene and 2,4,6-trinitroethylbenzene compared to a nitrocellulose binder plasticised with 2,4-dinitroethylbenzene and 1-nitramino-2,3-dinitroxypropane. The formation of nitric acid was more likely in a nitrocellulose binder plasticised with 2,4-dinitroethylbenzene and 2,4,6-trinitroethylbenzene compared to a nitrocellulose binder plasticised with 2,4-dinitroethylbenzene and 1-nitramino-2,3-dinitroxypropane. Force fields were parameterised for each binder component. Force fields were derived for the plasticiser molecules, the stabiliser ethyl centralite, nitrogen dioxide and nitrocellulose. The Lennard-Jones parameters were refined for each individual binder ingredient and the overall nitrocellulose binder systems until the simulated densities were within 2% of the experimental values

Polymeric drug delivery systems: aspects of core and shell of nanocarriers from polyesters, poly(ester amide)s or poly(2–oxazoline)s

Hydrophobe Wirkstoffe weisen häufig eine schlechten Bioverfügbarkeit und Transporteffizienz auf. Diese Nachteile können durch ein optimiertes Nanoträgersystem kompensiert werden. Hierfür sind polymerbasierte Mizellen und Nanopartikel mit einem hydrophoben Kern besonders geeignet. Die Personalisierung des jeweiligen Polymergrundgerüsts sollte jedoch unter Beachtung der kausalen Zusammenhänge erfolgen. In diesem Zusammenhang wurden in der vorliegenden Dissertation ausgewählte Kandidaten der Polyester, Polyesteramide und Poly(2-ethyl-2-oxazolin)e untersucht. Neben ihrer Synthese, wurden diese Materialien hinsichtlich ihrer Anwendung als Nanocarrier und Struktur–Eigenschafts–Beziehungen bewertet. Die konstante hydrophile-hydrophobe-Balance wurde für wohldefinierte Poly(ɛ–caprolacton)-Analoga mit unterschiedlicher Mikroarchitektur validiert. Trotz unterschiedlicher thermischer Polymereigenschaften wurden vielversprechende Nanopartikel mit gleicher Größe und ausgezeichneter Langzeitstabilität erhalten. Eine Polyesteramid-Bibliothek wurde durch die Polyaddition von acht Dicarbonsäuren und 2,2`-Bis(2-oxazoline) erzeugt. Im Anschluss wurden die geeigneten Materialien in einer Kompatibilitätsstudie mit dem hydrophoben, antientzündlichen Wirkstoff Indomethacin untersucht. Formulierbarkeit des Polymers, aber auch die Kompatibilität der Kernkomponenten in Bulk hatten beide einen signifikanten Einfluss auf die Qualität der beladenen Nanoträger. Die Einführung einer hydrophilen Stealth-Schale erfolgte im Makromonomeransatz durch Kombination der kationischen Ringöffnungspolymerization und einer kontrollierten, radikalischen Polymerisation. Resultierende Kern-Schale-Mizellen basierend auf dem hydrophoben Poly(methylmethacrylat)-Rückgrat und hydrophilien Seitenketten aus Oligo(2-ethyl-2-oxazolin) wurden in Abhängigkeit der variierenden Rückgrat-Endgruppe untersucht. Mittels intravitaler Mikroskopie wurde ein Endgruppeneinfluss auf die Leberzellspezifität in Mausstudien festgestellt

Investigating phosphate structural replacements through computational and experimental approaches

Bioisosteric replacements are used in drug design during lead generation and optimization processes with the aim to replace one functional group of a known molecule by another while retaining biological activity. The reason to use bioisosteric replacements are typically to optimize bioavailability or reducing toxicity. Phosphate groups represent a paradigm to study bioisosteric replacements. Protein-phosphate interaction plays a critical role during molecular recognition processes, and for example kinases represent one of the largest families of drug targets. However, some challenges exclude phosphate as a promising lead-like building block: i) charged phosphates do not cross molecular membranes; ii) some widely expressed proteins such as phosphatases easily hydrolyze phosphoric acid esters, which lead phosphate-containing ligands to lose their binding affinities before reaching their biological targets; iii) introduction of phosphate groups to parent scaffold is not easy. In the first part of the thesis work, I designed and implemented a computational protocol to mine information about phosphate structural replacements deposited in the Protein Data Bank. I constructed 116, 314, 271, and 42 sets of superimposed proteins where each set contains a reference protein to either POP, AMP, ADP, or ATP as well as a certain number of non-nucleotide ligands. 929 of such ligands are under study. The chemotypes that came out as structural replacements are diverse, ranging from common phosphate isosteres such as carboxyl, amide and squaramide to more surprising moieties such as benzoxaborole and aromatic ring systems. I exemplified some novel examples and interpreted the mechanism behind them. Local structural replacements are circumstance dependent: one chemical group valid in certain set-up cannot necessarily guarantee the success of another. The data from the study is available at http://86.50.168.121/phosphates_LSR.php. In the second part, I synthesized fifteen compounds retaining the adenosine moieties and bearing bioisosteric replacements of the phosphate at the ribose 5'-oxygen to test their stability toward human macro domain protein 1. These compounds are composed of either a squaryldiamide or an amide group as the bioisosteric replacement and/or as a linker. To these groups a variety of substituents were attached: phenyl, benzyl, pyridyl, carboxyl, hydroxy and tetrazolyl. Biological evaluation using differential scanning fluorimetry showed that four compounds stabilized human MDO1 at levels comparable to ADP and one at level comparable to AMP. Virtual screening was also run to identify MDO1 binding ligands. Among 20,000 FIMM database lead-like molecules, 39 compounds were selected for testing and eleven compounds found active based on ADPr and Poly-ADPr competition binding assay. The assay is however not well validated and a second confirmatory assay was conducted using calorimetry. To the best of my knowledge, this is the first report of non-endogenous ligands of the human MDO1. Altogether, this thesis highlights the versatility of molecular recognition processes that accompanies chemical replacements in compounds; this in turns shows the limits of the concepts of molecular similarity and classical bioisosterism that are based on the conservation of molecular interactions.Bioisosteeristä korvausta käytetään lääkeainekehityksessä johtolankamolekyylien tuottamisessa ja optimoinnissa. Tarkoitus on vaihtaa molekyylin funktionaalinen ryhmä toiseksi biologisen aktiivisuuden muuttumatta. Yleensä tavoitteena on parantaa biologista hyötyosuutta tai vähentää toksisuutta. Fosfaattiryhmää on tässä työssä käytetty esimerkkiryhmänä bioisosteerisiä korvauksia tutkittaessa. Väitöskirjatyön ensimmäisessä osassa suunnittelin ja toteutin tiedonlouhintaprotokollan etsiäkseni Protein Data Bank -tietokannasta korvaavia rakenteita fosfaattiryhmälle. Kokosin 116, 314, 271 ja 42 proteiiniryhmää, joissa kussakin on vertailumolekyylinä fosfaattiryhmän sisältävä POP, AMP, ADP tai ATP, ja lisäksi ei-nukleotidisiä ligandeja. Yhteensä 929 ei-nukleotidistä ligandia tutkittiin. Niistä löydettiin monipuolisesti fosfaattiryhmän korvaavia rakenteita, muun muassa yleisesti tunnettuja fosfaatin bioisosteerejä kuten karboksyyli, amidi ja squaramidi, mutta myös erikoisempia ryhmiä kuten bentsoksaboroli ja aromaattisia rengasrakenteita. Työssäni esittelen muutamia uusia rakenteita ja tulkitsen niiden vaikutusmekanismeja. Rakenteiden korvaaminen riippuu tilanteesta; yhteen tapaukseen sopiva korvaava ryhmä ei välttämättä toimi toisessa. Työn toisessa osassa syntetisoin 15 adenosiiniyhdistettä, joiden riboosiosan 5'-hapessa oleva fosfaattiryhmä on korvattu vaihtelevalla bioisosteerisellä ryhmällä. Bioisosteerisenä ryhmänä tai linkkerinä oli joko squaramidi- tai amidiryhmä. Yhdisteiden vakaus testattiin ihmisen MDO1-makrodomeeniproteiinin kanssa.Julkaisussa virheellinen verkkoaineiston ISBN 978-951-51-0045-0