<p> The solute carrier family (&ldquo;SLC&rdquo;) is a diverse group of membrane transporter proteins expressed ubiquitously throughout the human body. SLC members have been heavily implicated in Mendelian disease, and play an active role in the pathogenesis of many cancers. Further, several members of the SLC family have ligands and/or precise functions that have yet to be elucidated. As such, examining the structure and function relationships of this family can have significant implication in the study and drug design of serious disease. We explored these structure and function relationships in three specific SLC members, with the goal of applying a homology modeling approach to both tool compound discovery and the examination of disease mechanisms. This study highlights the importance of homology modeling both in the exploration of the role SLC members play in human disease, and in human health overall. </p><p>

<p> Molecular drug design begins with the identification of a problem to solve. This work identifies the growing resistance among human pathogens to current treatments. Once the problem is identified and understood, solutions must be proposed. This one is straight forward, we need new antimicrobial drugs. More specifically, we need to identify novel targets to inhibit. A large portion of antibiotics focus on disruption of macromolecular production while only a few target metabolic systems. Finally, you need to propose solutions based on the information gathered. In order to avoid existing resistance, it is important to avoid the macromolecular route and focus on metabolic enzymes. Preferably, the pathway would have little overlap or similarity with pathways found in the treatment organism. With this in mind, the non-mevalonate (NMA) pathway poses as a very good target for drug design. Many pathogens have been found to be strictly dependent on this pathway while it is absent in humans. Additionally, fosmidomycin has already been shown to inhibit this pathway. Initially thought to just inhibit the 1-deoxy-D-xylulose 5-phosphate (DXP) reductoisomerase (DXR), it has been shown to inhibit several enzymes along the path to a lesser extent. Ideally, this could be repeated or improve upon for future drug design.</p><p> With this in mind, the initial stages of the first two enzymes of the NMA pathway were examined utilizing quantum mechanical/molecular mechanical (QM/MM) techniques. The first enzyme was DXP synthase (DXS), which catalyzes a transketolase-like condensation of pyruvate and glyceraldehyde-3-phosphate to produce DXP. DXS and other transketolases are dependent on the thiamine diphosphate (TDP) cofactor, which must be deprotonated of the imidazolium C2 atom producing a highly reactive ylide. A tautomerization occurs prior to this deprotonation to prime the pyrimidinium ring N4 atom to perform the C2 abstraction. The question at hand was the identity of a general base to perform the N4 abstraction. The results favored a water-mediate mechanism with a higher than usual &Delta;Ez of 22.7 kcal/mol. An observation pertaining the tautomerization pertained to the aromaticity of the pyrimidine ring. Upon further investigation, aromaticity was found to play a significant role in the &Delta;E observed. Aromaticity might contribute 14.2 kcal/mol to the barrier height. This high energy would drive the reaction forward producing the ylide. </p><p> Investigation of the DXR enzyme followed this work. Initially, the work was going to focus on the 2 mechanisms proposed for activity, alpha-ketol rearrangement and retroaldol/ aldol mechanism. Subsequent publications involving secondary kinetic isotope effects (KIEs) add to the pile of evidence supporting the retro-aldol/aldol mechanism. So the project was retooled to investigate the energetic differences between two metal binding modes. The results of this work support a metal coordination across the C3-C4 bond, which eventually extends coordination to include the C2 oxygen. This conformation was help explain the tight binding effecting observation of the putative intermediates (transition states) and aldehyde intermediate. Additionally, as the C2-C3 mode consistently transfers a proton to the phosphate group of DXP or produces an elongated C-O bond, the C2-C3 mode would not be favorable.</p><p> Further investigations of these enzymes (e.g. completing the step begin, continuing through the reaction) could provide further illumination into the mechanism of action and possibly reveal new avenues of drug design. Examining the enzymes downstream in the NMA pathway might provide details of interest. Of particular interest is the radical reaction proposed for HDR/IspH. The final step of the pathway produces IDP and DMADP in a 4:1 proportion, which corresponds to the general system requirements for production of the long chain, branched isoprenoids. It would be interesting to compute the mechanism to see if energetics could provide further insights. Additionally, normal mode analysis coupled with vibrational subsystem analysis could identify allosteric sites for feedback sensitivity.</p><p>

<p> This dissertation contains investigations based on Molecular Dynamics (MD) of a variety of systems, from small atomic clusters to polymers in solution and in their condensed phases. The overall research is divided in three parts. First, I tested a new thermostat in the literature on the thermal equilibration of a small cluster of Lennard-Jones (LJ) atoms. The proposed thermostat is a Hamiltonian thermostat based on a logarithmic oscillator with the outstanding property that the mean value of its kinetic energy is constant independent of the mass and energy. I inspected several weak-coupling interaction models between the LJ cluster and the logarithmic oscillator in 3D. In all cases I show that this coupling gives rise to a kinetic motion of the cluster center of mass without transferring kinetic energy to the interatomic vibrations. This is a failure of the published thermostat because the temperature of the cluster is mainly due to vibrations in small atomic clusters This logarithmic oscillator cannot be used to thermostat any atomic or molecular system, small or large. </p><p> The second part of the dissertation is the investigation of the inherent structure of the polymer polyethylene glycol (PEG) solvated in three different solvents: water, water with 4% ethanol, and ethyl acetate. PEG with molecular weight of 2000 Da (PEG₂₀₀₀) is a polymer with many applications from industrial manufacturing to medicine that in bulk is a paste. However, its structure in very dilute solutions deserved a thorough study, important for the onset of aggregation with other polymer chains. I introduced a modification to the GROMOS 54A7 force field parameters for modeling PEG₂₀₀₀ and ethyl acetate. Both force fields are new and have now been incorporated into the database of known residues in the molecular dynamics package Gromacs. This research required numerous high performance computing MD simulations in the ARGO cluster of GMU for systems with about 100,000 solvent molecules. My findings show that PEG₂₀₀₀ in water acquires a ball-like structure without encapsulating solvent molecules. In addition, no hydrogen bonds were formed. In water with 4% ethanol, PEG₂₀₀₀ acquires also a ball-like structure but the polymer ends fluctuate folding outward and onward, although the general shape is still a compact ball-like structure. </p><p> In contrast, PEG₂₀₀₀ in ethyl acetate is quite elongated, as a very flexible spaghetti that forms kinks that unfold to give rise to folds and kinks in other positions along the polymer length. The behavior resembles an ideal polymer in a &thetas; solvent. A Principal Component Analysis (PCA) of the minima composing the inherent structure evidences the presence of two distinct groups of ball-like structures of PEG₂₀₀₀ in water and water with 4% ethanol. These groups give a definite signature to the solvated structure of PEG₂₀₀₀ in these two solvents. In contrast, PCA reveals several groups of avoided states for PEG₂₀₀₀ in ethyl acetate that disqualify the possibility of being an ideal polymer in a &thetas; solvent. </p><p> The third part of the dissertation is a work in progress, where I investigate the condensed phase of PEG₂₀₀₀ and study the interface between the condensed phase and the three different solvents under study. With a strategy of combining NPT MD simulations at different temperatures and pressures, PEG₂₀₀₀ condensed phase displays the experimental density within a 1% discrepancy at 300 K and 1 atm. This is a very encouraging result on this ongoing project. </p><p>

As a reliable, convenient, and advantageous tool in the theoretical investigations of bioorganic, inorganic, and organometallic chemistry, density functional theory (DFT) computations have provided chemists with numerous significant insights. The understanding of mechanisms of chemical reactions, and the design and development of catalysts have been greatly promoted by the employment of DFT. In this dissertation, the applications of DFT computations in the catalytic bioorganic, inorganic, and organometallic systems were studied. Phosphoramidate hydrolysis catalyzed by human histidine triad nucleotide binding protein 1 (hHint1) was investigated using a cluster-model DFT approach, and the key involvement of the histidine triad as a proton shuttle was discussed in the proposed mechanism. The IEFPCM-Bondi-B3LYP/BS1 methodology was demonstrated as a reliable, and time-saving model in computing the reduction potentials of transition metal complexes. Moderate accuracy (MAD = 0.233 V, mean absolute deviation) and good linear correlation (R2 = 0.93) between computed and experimental reduction potentials of the 49 studied species are osberved. The fluxionality of cyclohexenyl manganese tricarbonyl [(C6H9)Mn(CO)3] was investigated using DFT computations, which uncovered a previously uncharacterized “closed” Cs agostomer. The intramolecular oxidative amination of an alkene catalyzed by the extreme π-loading N-heterocyclic carbene pincer Tantalum(V) bis(imido) complex was also computationally analyzed, and the mechanisms of the formation of oxidative amination product, reduction product, and hydroamination product were investigated. The computational results are consistent with the experimentally observed product ratios and selectivity.

Yes / Research in graphene-based energy materials is a rapidly growing area. Many graphene-based energy applications involve interfacial processes. To enable advances in the design of these energy materials, such that their operation, economy, efficiency and durability is at least comparable with fossil-fuel based alternatives, connections between the molecular-scale structure and function of these interfaces are needed. While it is experimentally challenging to resolve this interfacial structure, molecular simulation and computational chemistry can help bridge these gaps. In this Review, we summarise recent progress in the application of computational chemistry to graphene-based materials for fuel cells, batteries, photovoltaics and supercapacitors. We also outline both the bright prospects and emerging challenges these techniques face for application to graphene-based energy materials in future. / veski

<p>The notion of autonomous laboratories is of much interest to the chemical science community.  Promises of increased efficiency and throughput of discovery, beyond that of automated platforms, has already begun to be fulfilled by autonomous continuous flow reactors and desktop robots.  For fully autonomous laboratories to be further realized, various components in these systems require automation.  Herein this work, are presented multiple data-driven statistical methods for automating and optimizing various chemical systems and processes.  Presented are: the development and deployment of a general stochastic optimization algorithm, a machine learning-based solvent selection pipeline for organic transformations, a generalized data-dependent scoring methodology for antibody assay development, the prototyping of an automated platform for ion-molecule reactions inside a linear ion trap, and a review on recent developments for machine learning and mass spectrometry.  In summary, these works present various components for furthering the automation of chemistry.</p>

The dramatic expansion of the electronics industry over the past 40 years has been based on the progressive reduction in size of the silicon-based semiconductor components of integrated circuits. The miniaturisation of semi-conductor circuits cannot, however, continue indefinitely, and we are rapidly approaching the stage where quantum effects will prevent further dramatic improvements in computer performance using existing technology. As a result, the field of molecular electronics, which seeks to identify and develop much smaller molecular analogues of the transistors that make up integrated circuits, has expanded rapidly over the past few years. Recent studies suggested that extended metal atom chains (EMAC) may have many potential applications in molecular electronics, but it is clear that this potential can only be realised if we establish a link between the fundamental electronic properties of these systems and the transport of electrons. For this reason the ultimate goal of this thesis is to relate the electronic structure of extended metal chains to their electron transport properties. We address the problem using non-equilibrium Green’s function, in conjugation with density functional theory. In the results sections of this thesis we present calculations on tricobalt, trichromium and trinickel chains. Our data suggested that in the trimetal chains, the dominant electron transport channel is the σ manifold, while the π systems establish the contact with the electrodes. The implication of this is that even when the highly polarized π channels are strongly rehybridised by the applied electric field, current flow is not affected. In the trichromium systems we find that the distortion of the chain away from the symmetric equilibrium structure does not perturb the current flow but rather enhances it. Our rather counter intuitive conclusion is therefore that ‘broken wires’ (highly unsymmetric) are more efficient conductors than their symmetric counterparts. We have performed calculation on longer penta- and heptacobalt structures chains to establish the extent to which longer structures attenuate the conductance. Our calculations show significant oscillations of the conductance due to development of a one-dimensional band structure about the Fermi level. The evolution of the electron transport properties in cobalt chains with different length is a complex one, but it is clear that narrowing the band gap in longer chains makes it increasingly likely that the Fermi level will be in resonance with one or more of the orbitals of the extended metal atom chain.

"Catalysts are involved at some stage in the manufacture process of virtually all commercially produced chemical product. Among the materials used as catalysts, metal oxides are one of the most used due to their versatility and wide range of physical properties. Identifying the principles of surface to adsorbate charge transfer is key to a better understanding of metal oxide materials as both catalysts and gas sensors. Using density functional theory (DFT), we modeled the adsorption of small molecules over stoichiometric and reduced metal oxide surfaces of group IV metals and quantify the effect of electron transfer upon adsorption. We found that charge transfer only occurs during the adsorption process of an adsorbate more electronegative than the surface. We also found a correlation between the work function of the metal oxide, and the ionic adsorption of the oxygen molecule. Mixed phase rutile/anatase catalysts show increased reactivity compared with the pure phases alone. However, the mechanism causing this effect is not fully understood. Using DFT and the +U correction we calculated the bands offsets between the phases taking into account the effect of the interface. We found rutile to have both higher conduction and valence band offsets than anatase, leading to an accumulation of electrons in the anatase phase accompanied by hole accumulation in the rutile phase. We also probed the electronic structure of our heterostructure and found a gap state caused by electrons localized in undercoordinated Ti atoms which were present within the interfacial region. Interfaces between bulk materials and between exposed surfaces both showed electron trapping at undercoordinated sites. Finally, we studied the effect of the size of gold nanoparticles in the catalytic properties of gold decorated titania surfaces. We found that the adsorption energy of several intermediates reactives in the CO oxidation and water gas shift reaction does not change with the size of the nanoparticles. In conclusion, the factor that affects the reactivity of the system is the density of undercoodinated gold atoms on the interface perimeter."

Electron scattering cross sections have been computed for pyridine and pyrimidine using the static-exchange approximation with model potential to account for dynamic electron correlation. To obtain well-converged orbitals, we have expanded all partial waves to a maximum angular momentum of l = 60 for both targets. We have obtained total cross sections for electron scattering energies to 20 eV. Both targets display similar features, namely a dipole-induced increase in the integrated cross section at scattering energies below 5 eV, and peaks corresponding to resonances in b1, a2, and b1 symmetries. These resonances were investigated through a Siegert eigenstate analysis and Breit-Wigner fit of the SECP eigenphase sums. They were also compared to the virtual orbitals obtained from a minimum basis set Hartree-Fock calculation on both targets. We consider electron scattering resonances from cis-diamminedichloroplatinum, [Pt(NH3)2Cl2], the ligand molecular species Cl2 (1Sigma+g ), and the isolated transition metal center Pt in a nondegenerate atomic state (1S) at the SECP level of theory. As a rigorous comparison to the single-state, single-configuration SECP level results of these smaller, yet electron dense targets, we have also considered scattering from ground state Cl2 and Pt in the 1S and 3D states in the multichannel configuration-interaction (MCCI) approximation originally developed for photoionization for scattering up to 10 eV. Photoionization cross sections and angular distributions in the recoil frame (RFPAD) and molecular frame (MFPAD) have been computed for inner-shell C 1s and Cl 2p ionization from the chloroalkanes chloromethane and chloroethane, with ionization leading to a variety of ionic fragment states. We have also computed valence level ionization from the nitro molecule nitromethane CH3NO2 leading to the dissociation of the CN bond. All of these calculations were performed in the frozen-core Hartree-Fock approximation. Even at this level of theory, we obtain computed results that compare well to the photoelectronphotoion coincidence measurements. The fullerene C20 is the smallest fullerene predicted to exist, with most relevant structural calculations suggesting the reduction of the icosahedral symmetry into one in which the target species possesses at maximum only a dihedral axis. We have computed positron scattering cross sections for the molecule in two low-symmetry structural isomers Ci and C2, within the HF approximation. Density functional expressions were used to incorporate important positron-electron interactions within the calculation. We have found similar cross sections and resonance features for both isomers, including a positron scattering resonance whose density is found within the framework of the fullerene cluster.

The abnormal expression or function of biological molecules, such as nucleic acids, proteins, or other small organic molecules, lead to the majority of diseases. Consequently, understanding the structure and function of these molecules through modeling can provide insight and perhaps suggest treatment for diseases. However, biologically relevant molecular phenomenon can vary vastly in the nature of their interactions and different classes of models are required to accommodate for this diversity. The objective of this thesis is to develop models for small molecules, amino acid peptides, and nucleic acids. A physical polarizable molecular mechanics model is described to accurately represent small molecules and single atom ions and applied to predict experimentally measurable thermodynamic properties such as hydration and binding free energies. A novel physical coarse-grain model based on Gay-Berne potentials and electrostatic multipoles has been developed for short peptides. The fraction of residues that adopt the alpha-helix conformation agrees with all-atom molecule dynamics results. Finally, a statistically-derived model based on sequence comparative sequence alignments is developed and applied to improve folding accuracy of RNA molecules. / text