Voltage-gated ion channels mediate electrical excitability of cellular membranes. Re- duced models of the voltage sensor (VS) of Kv channels produce insight into the electrostatic physics underlying the response of the highly positively charged S4 transmembrane domain to changes in membrane potential and other electrostatic parameters. By calculating the partition function computed from the electrostatic energy over translational and/or rotational degrees of freedom, I compute expectations of charge displacement, energetics, probability distributions of translation & rotation and Maxwell stress for arrangements of S4 positively charged residues and S2 & S3 negatively charged counter-charges; these computations can then be compared with experimental results to elucidate the role of various putative atomic level features of the VS. A "paddle" model (Jiang et al., 2003) is rejected on electrostatic grounds, owing to unfavorable energetics, insufficient charge displacement and excessive Maxwell stress. On the other hand, a "sliding helix" model (Catterall, 1986) with three local counter-charges, a protein dielectric coefficient of 4 and a 2/3 interval of counter-charge positioning relative to the S4 alpha-helix period of positive residues is electrostatically reasonable, comparing well with Shaker (Seoh et al., 1996). Lack of counter-charges destabilizes the S4 in the membrane; counter-charge interval helps determine the number and shape of energy barriers and troughs over the range of motion of the S4; and the local dielectric coefficient of the protein (S2, S3 & S4) constrains the height of energy maxima relative to the energy troughs. These "sliding helix" models compare favorably with experimental results for single & double mutant charge experiments on Shaker by Seoh et al. (1996). Single S4 positive charge mutants are predicted quite well by this model; single S2 or S3 negative counter-charge mutants are predicted less well; and double mutants for both an S4 charge and an S2 or S3 counter-charge are characterized least well by these electrostatic models (which do not include gating load, unlike their biological analogs). Further computational and experimental investigation of S2 & S3 counter-charge structure for voltage-gated ion channels is warranted.

A numerical study of flow of a shear thinning fluid through a pair of corrugated plates was carried out. The aim of the study was to observe and understand the behavior of the flow of shear thinning fluids through channels were the fluid is subjected to a periodic increase and decrease in cross-section area. Such conditions are frequently observed in the flow of blood through blood vessels, movement of lubricating oils through the ground during the oil extraction process, in the process industry. Since we are dealing with non-Newtonian fluids the non-linear terms in the constitutive equation have a significant affect on their behavior. The plates modeled for the study had a sinusoidal profile. A total of four different plates were with varying amplitude and wavelengths were simulated. The simulations were done both in two and three dimensional space. A wide range of Reynolds numbers were used for each plate. The Reynolds number used was a function of the half the average plate spacing (h) and the velocity. The range of Reynolds numbers used is 100 to 1000. The velocity profiles along the crest, trough and center lines were generated. It was observed that even at low velocities and low Reynolds numbers the shear stress at the wall was significant. It was also observed that even at low velocities and low Reynolds numbers reversed flow can occur near the regions where the profile of geometry is sinusoidal. Such behavior is a characteristic of shear thinning fluid.

A numerical study of flow of a shear thinning fluid through a pair of corrugated plates was carried out. The aim of the study was to observe and understand the behavior of the flow of shear thinning fluids through channels were the fluid is subjected to a periodic increase and decrease in cross-section area. Such conditions are frequently observed in the flow of blood through blood vessels, movement of lubricating oils through the ground during the oil extraction process, in the process industry. Since we are dealing with non-Newtonian fluids the non-linear terms in the constitutive equation have a significant affect on their behavior. The plates modeled for the study had a sinusoidal profile. A total of four different plates were with varying amplitude and wavelengths were simulated. The simulations were done both in two and three dimensional space. A wide range of Reynolds numbers were used for each plate. The Reynolds number used was a function of the half the average plate spacing (h) and the velocity. The range of Reynolds numbers used is 100 to 1000. The velocity profiles along the crest, trough and center lines were generated. It was observed that even at low velocities and low Reynolds numbers the shear stress at the wall was significant. It was also observed that even at low velocities and low Reynolds numbers reversed flow can occur near the regions where the profile of geometry is sinusoidal. Such behavior is a characteristic of shear thinning fluid.

A numerical study of flow of a shear thinning fluid through a pair of corrugated plates was carried out. The aim of the study was to observe and understand the behavior of the flow of shear thinning fluids through channels were the fluid is subjected to a periodic increase and decrease in cross-section area. Such conditions are frequently observed in the flow of blood through blood vessels, movement of lubricating oils through the ground during the oil extraction process, in the process industry. Since we are dealing with non-Newtonian fluids the non-linear terms in the constitutive equation have a significant affect on their behavior. The plates modeled for the study had a sinusoidal profile. A total of four different plates were with varying amplitude and wavelengths were simulated. The simulations were done both in two and three dimensional space. A wide range of Reynolds numbers were used for each plate. The Reynolds number used was a function of the half the average plate spacing (h) and the velocity. The range of Reynolds numbers used is 100 to 1000. The velocity profiles along the crest, trough and center lines were generated. It was observed that even at low velocities and low Reynolds numbers the shear stress at the wall was significant. It was also observed that even at low velocities and low Reynolds numbers reversed flow can occur near the regions where the profile of geometry is sinusoidal. Such behavior is a characteristic of shear thinning fluid.

A numerical study of flow of a shear thinning fluid through a pair of corrugated plates was carried out. The aim of the study was to observe and understand the behavior of the flow of shear thinning fluids through channels were the fluid is subjected to a periodic increase and decrease in cross-section area. Such conditions are frequently observed in the flow of blood through blood vessels, movement of lubricating oils through the ground during the oil extraction process, in the process industry. Since we are dealing with non-Newtonian fluids the non-linear terms in the constitutive equation have a significant affect on their behavior. The plates modeled for the study had a sinusoidal profile. A total of four different plates were with varying amplitude and wavelengths were simulated. The simulations were done both in two and three dimensional space. A wide range of Reynolds numbers were used for each plate. The Reynolds number used was a function of the half the average plate spacing (h) and the velocity. The range of Reynolds numbers used is 100 to 1000. The velocity profiles along the crest, trough and center lines were generated. It was observed that even at low velocities and low Reynolds numbers the shear stress at the wall was significant. It was also observed that even at low velocities and low Reynolds numbers reversed flow can occur near the regions where the profile of geometry is sinusoidal. Such behavior is a characteristic of shear thinning fluid.

abstract / Chemistry / Doctoral / Doctor of Philosophy

In recent decades, small molecules have been widely applied to the generation of functional ion transporters. Major discoveries disclosed in this thesis include a self-assembled chloride-dependent potassium channel candidate, a physiological chloride and bicarbonate dual-transporter, and a series of efficient synthetic ion transporters. In nature, K+ channels play an important role in Ca2+ signaling, volume regulation, secretion, proliferation, and migration. The extracellular K+ concentration (4 mM) is about 40 times lower than the intracellular K+ concentration (160 mM). The opening of K+ channels consequently generates an efflux of positive charge, which hyperpolarizes or repolarizes the cellular membrane. In this research, by using fluorescence assays, NMR and patch clamp experiments, compound ZHY-CM23 was found to self-assemble into a chloride-dependent K+ selective channel mediating K+ transport across lipid bilayers and cell membranes. In addition, the synthetic K+ channel formed by ZHY-CM23 was found to be capable of generating and modulating the membrane potential of liposomes and to significantly hyperpolarize the resting membrane potential of HEK 293 cells. This finding provides new insight into developing drugs for the treatment of severe human diseases caused by K+ channel malfunction, such as arrhythmia, neurological disorders and autoimmune diseases. Cystic fibrosis is a chronic recessive disease resulting from the loss of function mutations in the gene encoding of the cystic fibrosis transmembrane conductance regulator (CFTR), a member of the ABC family of membrane transporters. Recent findings reveal that restoring bicarbonate transport might be useful for the treatments of the underlying defect in cystic fibrosis. On the basis of fluorescence assays, NMR and short circuit current experiments, the small molecule ZHY-CM11 has been discovered to not only act as a bicarbonate transporter in lipid membranes, but also to induce chloride-dependent bicarbonate secretion in cultured calu-3 epithelia. It is a promising lead compound to be developed for the treatment of cystic fibrosis and other diseases related to chloride and bicarbonate transport defects. Through structural modifications on the bioactive ion channels and the transporters ZHY-CM23 and ZHY-CM11, some valuable information on the structure-activity relationship has been obtained, and a series of potentially biologically applicable synthetic ion transporters have been discovered. / published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

Thesis (Ph.D.)--University of Kentucky, 2007. / Adviser: Robert Dahlstrom. Includes bibliographical references.

Thesis (Ph.D.)--Virginia Polytechnic Institute and State University, 2007. / Advisers: James R. Brown, Noreen Klein. Includes bibliographical references.

Thesis (Ph. D., Civil Engineering)--University of Idaho, December 2008. / Major professor: Peter Goodwin. Includes bibliographical references. Also available online (PDF file) by subscription or by purchasing the individual file.