http://hdl.handle.net/1903/11812 2013-05-21T06:45:34Z http://hdl.handle.net/1903/13845 Title: Simulations of nonuniform fluids with long-ranged and short-ranged interactions Authors: Liu, Shule Abstract: The study of nonuniform fluids is of great importance in many areas of chemistry, biophysics,and materials science. Computer simulations of model systems have provided great insight into fundamental physical issues. We have studied two model systems: amphiphiles on a hydrophilic silica surface and charge overcompensation at the boundary of a colloid by multivalent ions. In the first model system, the organization of propionitrile and methanol near the surface has been studied via simulations. Both molecules can form highly organized bilayer-like structure near the surface. For propionitrile molecules, inside the bilayer-like structure hydrocarbon molecules intertwine with each other and form a closely packed structure. For methanol, molecules are strongly bonded to the silica surface with hydrogen bonds, resulting in much stronger hydrogen bonding than in the bulk and extremely slow dynamics. In our second model system, we use the local molecular field (LMF) theory to calculate the structure and solvation free energy of the system with a highly charged colloid immersed in trivalent salt. A mimic system with only short-ranged interactions was constructed using the LMF theory. By solving the LMF equation self-consistently, we have obtained the correct structure that indicates overcharging, where the charge of the colloid is overcompensated by the charge of trivalent ions. Then by taking a series of steps in a thermodynamic cycle, we have also calculated the solvation free energy of the colloid, using only results from the mimic system, and found very good agreement with more costly calculations carried out in the full long-ranged system. 2012-01-01T00:00:00Z http://hdl.handle.net/1903/13838 Title: Microwave-Supported Acid Hydrolysis for Proteomics Authors: Cannon, Joe Abstract: Our goal is to develop, optimize and demonstrate workflows that incorporate rapid Asp-selective chemical proteolysis into proteomic studies of complex mixtures. This can be further divided into several specific aims. The first aim is to develop and optimize the sample preparation, mass spectrometric, and bioinformatic methods required for complex mixture analysis of peptides resulting from acid digestion both in solution and in polyacrylamide gels. Second, the optimized methods will be applied to three model systems. In the first application, the large peptides derived from microwave-supported acid hydrolysis of human ribosomes isolated from MCF-7 breast cancer cells are analyzed. Secondly, acid hydrolysis will be applied to characterize Lys63 linkages in polyubiquitins. Finally, all the above methods will be combined for the analysis of extracellular vesicles shed by myeloid derived suppressor cells from a murine mammary carcinoma model. After optimizing the mass spectrometric and bioinformatic methods required for analysis of peptides resulting from acid hydrolysis, the most comprehensive analysis using this digestion technique to date was achieved both for in gel and in solution analysis. In gel digestion resulted in identification of over twelve hundred peptides representing 642 proteins, and in solution digestion via mass biased partitioning allowed identification of over 300 proteins. Mass biased partitioning also resulted in two distinct peptide populations from the high and low mass analyses implemented. Nearly 90% of the predicted human ribosomal proteins were identified after acid hydrolysis. High resolution analysis of both precursor and product ions resulted in an average sequence coverage of 46% among identified proteins. It was also demonstrated that microwave-supported acid hydrolysis facilitates a more informative method for analysis of Lys63 linked polyubiquitin. After acid hydrolysis, ~629 Da mass shifts were found to be indicative of isopeptides. These isopeptides were easily identified from complex mixtures using tandem mass spectrometry and diagnostic b ions. Extracellular vesicles from a murine carcinoma model were then analyzed using in gel microwave-supported acid hydrolysis, mass biased partitioning after in solution digestion, and the sample was interrogated for the presence of ubiquitinated peptides. 2012-01-01T00:00:00Z http://hdl.handle.net/1903/13836 Title: Exploring Equilibrium Systems with Nonequilibrium Simulations Authors: Ballard, Andrew James Abstract: Equilibrium sampling is at the core of computational thermodynamics, aiding our understanding of various phenomena in the natural sciences including phase coexistence, molecular solvation, and protein folding. Despite the widespread development of novel sampling strategies over the years, efficient simulation of large complex systems remains a challenge. While the majority of current methods such as simulated tempering, replica exchange, and Monte Carlo methods rely solely on the use of equilibrium techniques, recent results in statistical physics have uncovered the possibility to sample equilibrium states through nonequilibrium simulations. In our first study we present a new replica exchange sampling strategy, "Replica Exchange with Nonequilibrium Switches," which uses nonequilibrium simulations to enhance equilibrium sampling. In our method, trial swap configurations between replicas are generated through nonequilibrium switching simulations which act to drive the replicas towards each other in phase space. By means of these switching simulations we can increase an effective overlap between replicas, enhancing the probability that these moves are accepted and ultimately leading to more effective sampling of the underlying energy landscape. Simulations on model systems reveal that our method can be beneficial in the case of low replica overlap, able to match the efficiency of traditional replica exchange while using fewer processors. We also demonstrate how our method can be applied for the calculation of solvation free energies. In a second, separate study, we investigate the dynamics leading to the dissociation of Na-Cl in water. Here we employ tools of rare event sampling to deduce the role of the surrounding water molecules in promoting the dissociation of the ion pair. We first study the thermodynamic forces leading to dissociation, finding it to be driven energetically and opposed entropically. In further analysis of the system dynamics, we deduce a) the spatial extent over which solvent fluctuations influence dissociation, b) the role of sterics and electrostatics, and c) the importance of inertia in enhancing the reaction probability. 2012-01-01T00:00:00Z http://hdl.handle.net/1903/13826 Title: DIRHODIUM CAPROLACTAMATE CATALYZED OXIDATIONS BY TERT-BUTYL HYDROPEROXIDE. FROM MECHANISMS TO NEW METHODOLOGIES Authors: Ratnikov, Maxim O. Abstract: Dirhodium caprolactamate, Rh₂(cap)₄, is a very efficient catalyst for the generation of the <italic>tert</italic>-butylperoxy radical from <italic>tert</italic>-butyl hydroperoxide, and the <italic>tert</italic>-butylperoxy radical is a highly effective oxidant for phenols and anilines. These reactions are performed with 70% aqueous <italic>tert</italic>-butyl hydroperoxide using dirhodium caprolactamate in amounts as low as 0.01 mol % in toluene and chlorobenzene to oxidize <italic>para</italic>-substituted phenols to 4-(<italic>tert</italic>-butyldioxy)cyclohexadienones. Electron rich and electron poor phenolic substrates undergo selective oxidation in good to excellent yields, but steric influences from bulky para substituents force oxidation onto the ortho position resulting in <italic>ortho</italic>-quinones. Comparative results with RuCl₂(PPh₃)₃ and CuI are provided, and mechanistic comparisons are made between these catalysts that are based on diastereoselectivity (reactions with estrone), regioselectivity (reactions with <italic>p</italic>-<italic>tert</italic>-butylphenol) and chemoselectivity in the formation of 4-(<italic>tert</italic>- butyldioxy)cyclohexadienones. The data obtained are consistent with hydrogen atom abstraction by the <italic>tert</italic>-butylperoxy radical followed by radical combination between the phenoxy radical and the <italic>tert</italic>-butylperoxy radical. Under similar reaction conditions <italic>para</italic>-substituted anilines are oxidized to nitroarenes in good yield. An efficient one-pot tandem sequence forming heterocycles is developed. The method consists of an efficient phenol oxidation with inexpensive T-HYDRO catalyzed by dirhodium caprolactamate followed by Bronsted acid promoted cyclization. Substrate scope includes uses of L-tyrosine ester and dipeptide derivatives. Application of chiral phosphoric acids for asymmetric cyclization is discussed. Previously unreported peroxide cleavage with TiCl₄ enables a rapid synthesis of cleroindidin F. A general mechanism is proposed for transition metal catalyzed oxidative Mannich reactions of <italic>N</italic>-methylanilines with <italic>tert</italic>-butyl hydroperoxide (TBHP) as an oxidant. Kinetic data and isotope labeling of the <italic>N</italic>-methyl group suggest a rapid equilibrium between an iminum ion and solvent or TBHP preceding Mannich addition. Linear free-energy relationship (LFER) analysis, kinetic and product isotope effects, and utilization of radical clock substituents establish <italic>tert</italic>-butylperoxy radicals as an oxidant in dirhodium(II) caprolactamate [Rh₂(cap)₄] catalyzed oxidations of <italic>N,N</italic>-dialkylaniline by TBHP. Isotope effects measured for various transition metal salts reveal a general role of alternative catalysts as initiators of TBHP decomposition in <italic>N,N</italic>-dialkylaniline oxidations. New mechanistic insights led the development of the novel FeCl₃ catalyzed oxidative Mannich reaction. 2012-01-01T00:00:00Z