No description available.

No description available.

No description available.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Earth and Planetary Sciences, 1980. / Supervised by Nicholas P. Fofonoff. Vita. Includes bibliographical references (leaves 156-158).

Nickel based superalloys have superior high temperature mechanical strength, corrosion and creep resistance in harsh environments and found applications in the hot sections as turbine blades and turbine discs in jet engines and gas generator turbines in the aerospace and energy industries. The efficiency of these turbine engines depends on the turbine inlet temperature, which is determined by the high temperature strength and behavior of these superalloys. The microstructure of nickel based superalloys usually contains coherently precipitated gamma prime (?) Ni3Al phase within the random solid solution of the gamma () matrix, with the ? phase being the strengthening phase of the superalloys. How the alloying elements partition into the and ? phases and especially in the site occupancy behaviors in the strengthening ? phases play a critical role in their high temperature mechanical behaviors. The goal of this dissertation is to study the site substitution behavior of the major alloying elements including Cr, Co and Ti through first principles based calculations. Site substitution energies have been calculated using the anti-site formation, the standard defect formation formalism, and the vacancy formation based formalism. Elements such as Cr and Ti were found to show strong preference for Al sublattice, whereas Co was found to have a compositionally dependent site preference. In addition, the interaction energies between Cr-Cr, Co-Co, Ti-Ti and Cr-Co atoms have also been determined. Along with the charge transfer, chemical bonding and alloy chemistry associated with the substitutions has been investigated by examining the charge density distributions and electronic density of states to explain the chemical nature of the site substitution. Results show that Cr and Co atoms prefer to be close by on either Al sublattice or on a Ni-Al mixed lattice, suggesting a potential tendency of Cr and Co segregation in the ? phase.

Folding free energy of a protein is a delicate balance between stabilizing and destabilizing non-covalent itneractions. In this work, we decompose folding free energy into physically meaningful contributions, in which we aim to find general trends. Empirical potential is used to calculate interaction energy between all protein fragments, which are classified based on their dominant term in multipolar expansion. Calculations are done using 1200 non-redundant structures from PDB database. Based on the general trends found in interactions between these fragments, we attempt to better understand relationships between interaction energies calculated using computational chemistry methods and their corresponding free energy contributions on stabilization. 1

The small- and intermediate-conductance Ca2+ activated K + (SK/IK) channels play a fundamental role in the regulation of neurons in the central nervous system. In animal models, SK/IK channel positive modulators have been shown to be effective in reducing the symptoms of neurological diseases such as ataxia. Ataxia is a lethal neurological rare disease characterized by lack of balance and incoordination of muscle movements, often as a result of cerebellar or spinocerebellar neurodegeneration. SK/IK channel modulators have been developed over the past few decades. Currently available modulators are often weak in potency. Lack of knowledge about the binding site for the compounds is the main reason hindering the development of more potent and effective therapeutics targeting SK channels. Dr. Zhang and his colleagues recently discovered the binding pocket for these positive modulators of SK/IK channels. This pocket is located at the interface between the channel and calmodulin. Dr. Zhang and his colleagues performed screening of a large number of compounds in silico, to find those fitting into the binding pocket. I performed electrophysiological recordings to evaluate the efficacy and the potency of these modulators on SK2 channels. We discovered a correlation between the total binding energy values calculated from the structures and the potencies determined from electrophysiological recording.

<p>Malaria is a widespread disease caused by parasites of the genus <i>Plasmodium</i>. Each year 500 million clinical cases are reported resulting in over one million casualties. The most lethal species, <i>P. falciparum</i>, accounts for ~90% of the fatal cases and has developed resistance to chloroquine. The resistant strains are a major problem and calls for novel drugs.</p><p>In this thesis, the process of computational inhibitor design is illustrated through the development of <i>P. falciparum</i> aspartic protease inhibitors. These proteases, called plasmepsins, are part of the hemoglobin degradation chain. The hemoglobin is degraded during the intraerythrocytic cycle and serves as the major food source. By inhibiting plasmepsins the parasites can be killed by starvation.</p><p>Novel inhibitors with very high affinity were found by using a combination of computational and synthetic chemistry. These inhibitors were selective and did not display any activity on human cathepsin D. The linear interaction energy (LIE) method was utilized in combination with molecular dynamics (MD) simulations to estimate free energies of binding. The MD simulations were also used to characterize the enzyme–inhibitor interactions and explain the binding on a molecular level.</p><p>The influence of the partial charge model on binding free energy calculations with the LIE method was assessed. Two semiempirical and six <i>ab initio</i> quantum chemical charge derivation schemes were evaluated. It was found that the fast semiempirical charge models are equally useful in free energy calculations with the LIE method as the rigorous <i>ab initio</i> charge models.</p>

Admixtures like reactants and byproducts are solublenon-crystallizing compounds that can be present in industrialsolutions and affect crystallization of the main substance.This thesis provides experimental and molecular modellingresults on the influence of admixtures on crystal nucleation ofvanillin (VAN). Seven admixtures: acetovanillone (AVA),ethylvanillin (EVA), guaiacol (GUA), guaethol (GUE), 4-hydroxy-acetophenone (HAP), 4-hydroxy-benzaldehyde (HBA), andvanillic acid (VAC) have been used in this study. Classicalnucleation theory is used as the basis to establish arelationship between experimental induction time andsupersaturation, nucleation temperature, and interfacialenergy. A novel multicell device is designed, constructed, andused to increase the experimental efficiency in thedetermination of induction times by using 15 nucleation cellsof small volumes simultaneously. In spite of the largevariation observed in the experiments, the solid-liquidinterfacial energy for each VAN-admixture system can beestimated with an acceptable statistical confidence. At 1 mole% admixture concentration, the interfacial energy is increasedin the presence of GUA, GUE, and HBA, while it becomes lower inthe presence of the other admixtures. As the admixtureconcentration increases from 1 to 10 mole %, the interfacialenergy also increases. The interfacial energies obtained are inthe range 7-10 mJ m-2. Influence of admixtures on metastable zone widthand crystal aspect ratio of VAN is also presented. Theexperimental results show that the admixtures studied arepotential modifiers of the nucleation of VAN. Molecularmodelling by the program Cerius2 is used to identify the likelycrystal growth faces. Two approaches, the surface adsorptionand the lattice integration method, are applied to estimatequantitatively the admixture-crystal interaction energy on thedominating crystal faces of VAN,i.e., {0 0 1} and {1 0 0}. However, a simple and clearcorrelation between the experimental values of interfacialenergy and the calculated interaction energies cannot beidentified. A qualitative structural analysis reveals a certainrelationship between the molecular structure of admixtures andtheir effect on nucleation. The determination of the influenceof admixtures on nucleation is still a challenge. However, themolecular and crystal structural approach used in this thesiscan lead to an improved fundamental understanding ofcrystallization processes. Keywords: Crystallization,nucleation, vanillin, admixtures, additives, impurities,induction time, interfacial energy, molecular modelling,interaction energy.

Malaria is a widespread disease caused by parasites of the genus Plasmodium. Each year 500 million clinical cases are reported resulting in over one million casualties. The most lethal species, P. falciparum, accounts for ~90% of the fatal cases and has developed resistance to chloroquine. The resistant strains are a major problem and calls for novel drugs. In this thesis, the process of computational inhibitor design is illustrated through the development of P. falciparum aspartic protease inhibitors. These proteases, called plasmepsins, are part of the hemoglobin degradation chain. The hemoglobin is degraded during the intraerythrocytic cycle and serves as the major food source. By inhibiting plasmepsins the parasites can be killed by starvation. Novel inhibitors with very high affinity were found by using a combination of computational and synthetic chemistry. These inhibitors were selective and did not display any activity on human cathepsin D. The linear interaction energy (LIE) method was utilized in combination with molecular dynamics (MD) simulations to estimate free energies of binding. The MD simulations were also used to characterize the enzyme–inhibitor interactions and explain the binding on a molecular level. The influence of the partial charge model on binding free energy calculations with the LIE method was assessed. Two semiempirical and six ab initio quantum chemical charge derivation schemes were evaluated. It was found that the fast semiempirical charge models are equally useful in free energy calculations with the LIE method as the rigorous ab initio charge models.