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Molecular dynamics (MD) simulations provide a particularly useful approach to understanding conformational change in biomolecular systems. MD simulations provide an atomistic, physics-based description of the motions accessible to biomolecular systems on the pico- to micro-second timescale, yielding important insight into the free energy of the system, the dynamical stability of contacts and the role of correlated motions in directing the motions of the system. In this thesis, I use molecular dynamics simulations to provide molecular mechanisms that rationalize structural, thermodynamic, and mutation data on the interactions between the lac repressor headpiece and its O1 operator DNA as well as the ERK2 protein kinase. I performed molecular dynamics simulations of the lac repressor headpiece - O1 operator complex at the natural angle as well as at under- and overbent angles to assess the factors that determine the natural DNA bending angle. I find both energetic and entropic factors contribute to recognition of the natural angle. At the natural angle the energy of the system is minimized by optimization of protein-DNA contacts and the entropy of the system is maximized by release of water from the protein-DNA interface and decorrelation of protein motions. To identify the mechanism by which mutations lead to auto-activation of ERK2, I performed a series of molecular dynamics simulations of ERK1/2 in various stages of activation as well as the constitutively active Q103A, I84A, L73P and R65S ERK2 mutants. My simulations indicate the importance of domain closure for auto-activation and activity regulation. My results enable me to predict two loss-of-function mutants of ERK2, G83A and Q64C, that have been confirmed in experiments by collaborators. One of the powerful capabilities of MD simulations in biochemistry is the ability to find low free energy pathways that connect and explain disparate structural data on biomolecular systems. An extention of the targeted molecular dynamics technique using constraints on internal coordinates will be presented and evaluated. The method gives good results for the alanine dipeptide, but breaks down when applied to study conformational changes in GroEL and adenylate kinase.
ContributorsBarr, Daniel Alan (Author) / van der Vaart, Arjan (Thesis advisor) / Matyushov, Dmitry (Committee member) / Wolf, George (Committee member) / Shumway, John (Committee member) / Arizona State University (Publisher)
Created2011
Description
The properties of materials depend heavily on the spatial distribution and connectivity of their constituent parts. This applies equally to materials such as diamond and glasses as it does to biomolecules that are the product of billions of years of evolution. In science, insight is often gained through simple models with characteristics that are the result of the few features that have purposely been retained. Common to all research within in this thesis is the use of network-based models to describe the properties of materials. This work begins with the description of a technique for decoupling boundary effects from intrinsic properties of nanomaterials that maps the atomic distribution of nanomaterials of diverse shape and size but common atomic geometry onto a universal curve. This is followed by an investigation of correlated density fluctuations in the large length scale limit in amorphous materials through the analysis of large continuous random network models. The difficulty of estimating this limit from finite models is overcome by the development of a technique that uses the variance in the number of atoms in finite subregions to perform the extrapolation to large length scales. The technique is applied to models of amorphous silicon and vitreous silica and compared with results from recent experiments. The latter part this work applies network-based models to biological systems. The first application models force-induced protein unfolding as crack propagation on a constraint network consisting of interactions such as hydrogen bonds that cross-link and stabilize a folded polypeptide chain. Unfolding pathways generated by the model are compared with molecular dynamics simulation and experiment for a diverse set of proteins, demonstrating that the model is able to capture not only native state behavior but also partially unfolded intermediates far from the native state. This study concludes with the extension of the latter model in the development of an efficient algorithm for predicting protein structure through the flexible fitting of atomic models to low-resolution cryo-electron microscopy data. By optimizing the fit to synthetic data through directed sampling and context-dependent constraint removal, predictions are made with accuracies within the expected variability of the native state.
ContributorsDe Graff, Adam (Author) / Thorpe, Michael F. (Thesis advisor) / Ghirlanda, Giovanna (Committee member) / Matyushov, Dmitry (Committee member) / Ozkan, Sefika B. (Committee member) / Treacy, Michael M. J. (Committee member) / Arizona State University (Publisher)
Created2011
Description
Over the past century in the southwestern United States human actions have altered hydrological processes that shape riparian ecosystems. One change, release of treated wastewater into waterways, has created perennial base flows and increased nutrient availability in ephemeral or intermittent channels. While there are benefits to utilizing treated wastewater for environmental flows, there are numerous unresolved ecohydrological issues regarding the efficacy of effluent to sustain groundwater-dependent riparian ecosystems. This research examined how nutrient-rich effluent, released into waterways with varying depths to groundwater, influences riparian plant community development. Statewide analysis of spatial and temporal patterns of effluent generation and release revealed that hydrogeomorphic setting significantly influences downstream riparian response. Approximately 70% of effluent released is into deep groundwater systems, which produced the lowest riparian development. A greenhouse study assessed how varying concentrations of nitrogen and phosphorus, emulating levels in effluent, influenced plant community response. With increasing nitrogen concentrations, vegetation emerging from riparian seed banks had greater biomass, reduced species richness, and greater abundance of nitrophilic species. The effluent-dominated Santa Cruz River in southern Arizona, with a shallow groundwater upper reach and deep groundwater lower reach, served as a study river while the San Pedro River provided a control. Analysis revealed that woody species richness and composition were similar between the two systems. Hydric pioneers (Populus fremontii, Salix gooddingii) were dominant at perennial sites on both rivers. Nitrophilic species (Conium maculatum, Polygonum lapathifolium) dominated herbaceous plant communities and plant heights were greatest in effluent-dominated reaches. Riparian vegetation declined with increasing downstream distance in the upper Santa Cruz, while patterns in the lower Santa Cruz were confounded by additional downstream agricultural input and a channelized floodplain. There were distinct longitudinal and lateral shifts toward more xeric species with increasing downstream distance and increasing lateral distance from the low-flow channel. Patterns in the upper and lower Santa Cruz reaches indicate that water availability drives riparian vegetation outcomes below treatment facilities. Ultimately, this research informs decision processes and increases adaptive capacity for water resources policy and management through the integration of ecological data in decision frameworks regarding the release of effluent for environmental flows.
ContributorsWhite, Margaret Susan (Author) / Stromberg, Juliet C. (Thesis advisor) / Fisher, Stuart G. (Committee member) / White, Dave (Committee member) / Holway, James (Committee member) / Wu, Jianguo (Committee member) / Arizona State University (Publisher)
Created2011
Description
Conformational changes in biomolecules often take place on longer timescales than are easily accessible with unbiased molecular dynamics simulations, necessitating the use of enhanced sampling techniques, such as adaptive umbrella sampling. In this technique, the conformational free energy is calculated in terms of a designated set of reaction coordinates. At the same time, estimates of this free energy are subtracted from the potential energy in order to remove free energy barriers and cause conformational changes to take place more rapidly. This dissertation presents applications of adaptive umbrella sampling to a variety of biomolecular systems. The first study investigated the effects of glycosylation in GalNAc2-MM1, an analog of glycosylated macrophage activating factor. It was found that glycosylation destabilizes the protein by increasing the solvent exposure of hydrophobic residues. The second study examined the role of bound calcium ions in promoting the isomerization of a cis peptide bond in the collagen-binding domain of Clostridium histolyticum collagenase. This study determined that the bound calcium ions reduced the barrier to the isomerization of this peptide bond as well as stabilizing the cis conformation thermodynamically, and identified some of the reasons for this. The third study represents the application of GAMUS (Gaussian mixture adaptive umbrella sampling) to on the conformational dynamics of the fluorescent dye Cy3 attached to the 5' end of DNA, and made predictions concerning the affinity of Cy3 for different base pairs, which were subsequently verified experimentally. Finally, the adaptive umbrella sampling method is extended to make use of the roll angle between adjacent base pairs as a reaction coordinate in order to examine the bending both of free DNA and of DNA bound to the archaeal protein Sac7d. It is found that when DNA bends significantly, cations from the surrounding solution congregate on the concave side, which increases the flexibility of the DNA by screening the repulsion between phosphate backbones. The flexibility of DNA on short length scales is compared to the worm-like chain model, and the contribution of cooperativity in DNA bending to protein-DNA binding is assessed.
ContributorsSpiriti, Justin Matthew (Author) / van der Vaart, Arjan (Thesis advisor) / Chizmeshya, Andrew (Thesis advisor) / Matyushov, Dmitry (Committee member) / Fromme, Petra (Committee member) / Arizona State University (Publisher)
Created2011
Description
Driven by concern over environmental, economic and social problems, small, place based communities are engaging in processes of transition to become more sustainable. These communities may be viewed as innovative front runners of a transition to a more sustainable society in general, each one, an experiment in social transformation. These experiments present learning opportunities to build robust theories of community transition and to create specific, actionable knowledge to improve, replicate, and accelerate transitions in real communities. Yet to date, there is very little empirical research into the community transition phenomenon. This thesis empirically develops an analytical framework and method for the purpose of researching community transition processes, the ultimate goal of which is to arrive at a practice of evidence based transitions. A multiple case study approach was used to investigate three community transitions while simultaneously developing the framework and method in an iterative fashion. The case studies selected were Ashton Hayes, a small English village, BedZED, an urban housing complex in London, and Forres, a small Scottish town. Each community was visited and data collected by interview and document analysis. The research design brings together elements of process tracing, transformative planning and governance, sustainability assessment, transition path analysis and transition management within a multiple case study envelope. While some preliminary insights are gained into community transitions based on the three cases the main contribution of this thesis is in the creation of the research framework and method. The general framework and method developed has potential for standardizing and synthesizing research of community transition processes leading to both theoretical and practical knowledge that allows sustainability transition to be approached with confidence and not just hope.
ContributorsForrest, Nigel (Author) / Wiek, Arnim (Thesis advisor) / Golub, Aaron (Thesis advisor) / Redman, Charles (Committee member) / White, Dave (Committee member) / Arizona State University (Publisher)
Created2011
Description
The sacred San Francisco Peaks in northern Arizona have been at the center of a series of land development controversies since the 1800s. Most recently, a controversy arose over a proposal by the ski area on the Peaks to use 100% reclaimed water to make artificial snow. The current state of the San Francisco Peaks controversy would benefit from a decision-making process that holds sustainability policy at its core. The first step towards a new sustainability-focused deliberative process regarding a complex issue like the San Francisco Peaks controversy requires understanding the issue's origins and the perspectives of the people involved in the issue. My thesis provides an historical analysis of the controversy and examines some of the laws and participatory mechanisms that have shaped the decision-making procedures and power structures from the 19th century to the early 21st century.
ContributorsMahoney, Maren (Author) / Hirt, Paul W. (Thesis advisor) / Tsosie, Rebecca (Committee member) / White, Dave (Committee member) / Arizona State University (Publisher)
Created2011
Description
The use of synthetic cathinones or "bath salts" has risen dramatically in recent years with one of the most popular being Methylendioxypyrovalerone (MDPV). Following the temporary legislative ban on the sale and distribution of this compound , a multitude of other cathinone derivatives have been synthesized. The current study seeks to compare the abuse potential of MDPV with one of the emergent synthetic cathinones 4-methylethcathinone (4-MEC), based on their respective ability to lower current thresholds in an intracranial self-stimulation (ICSS) paradigm. Following acute administration (0.1, 0.5, 1 and 2 mg/kg i.p.) MDPV was found to significantly lower ICSS thresholds at all doses tested (F4,35=11.549, p<0.001). However, following acute administration (0.3,1,3,10,30 mg/kg i.p) 4-MEC produced no significant ICSS threshold depression (F5,135= 0.622, p = 0.684). Together these findings suggest that while MDPV may possess significant abuse potential, other synthetic cathinones such as 4-MEC may have a drastically reduced potential for abuse.
ContributorsWegner, Scott Andrew (Author) / Olive, M. Foster (Thesis director) / Presson, Clark (Committee member) / Sanabria, Federico (Committee member) / Barrett, The Honors College (Contributor) / Department of Chemistry and Biochemistry (Contributor) / Department of Psychology (Contributor)
Created2013-05
Description
Despite similar climate, ecosystem, and population size, the cities of Hermosillo, Mexico and Mesa, USA manage their water very differently. Mesa has a stable and resilient system organized around state and federal regulations. Hermosillo, after rapidly industrializing, has not been able to cope with climate change and long-term drought conditions. Water distribution statistics, stakeholders, policy structure, and government organization were combined in an organizational framework to compare the practices of the two cities. These inputs were weighed against the outcomes and the sustainability of each system. While Mesa is part of a massive metropolitan area, Hermosillo is still developing into a metropolitan center and does not have access to the same infrastructure and resources. In Hermosillo local needs are frequently discounted in favor of broad political goals.
ContributorsMoe, Rud Lamb (Author) / Chhetri, Netra (Thesis director) / White, Dave (Committee member) / Robles-Morua, Agustin (Committee member) / Barrett, The Honors College (Contributor) / School of Earth and Space Exploration (Contributor) / School of Sustainability (Contributor) / School of Geographical Sciences and Urban Planning (Contributor)
Created2013-05
Description
Accumulating evidence implicates exposure to adverse childhood experiences in the development of hypocortisolism in the long-term, and researchers are increasingly examining individual-level mechanisms that may underlie, exacerbate or attenuate this relation among at-risk populations. The current study takes a developmentally and theoretically informed approach to examining episodic childhood stressors, inherent and voluntary self-regulation, and physiological reactivity among a longitudinal sample of youth who experienced parental divorce. Participants were drawn from a larger randomized controlled trial of a preventive intervention for children of divorce between the ages of 9 and 12. The current sample included 159 young adults (mean age = 25.5 years; 53% male; 94% Caucasian) who participated in six waves of data collection, including a 15-year follow-up study. Participants reported on exposure to negative life events (four times over a 9-month period) during childhood, and mothers rated child temperament. Six years later, youth reported on the use of active and avoidant coping strategies, and 15 years later, they participated in a standardized psychosocial stress task and provided salivary cortisol samples prior to and following the task. Path analyses within a structural equation framework revealed that a multiple mediation model best fit the data. It was found that children with better mother-rated self-regulation (i.e. low impulsivity, low negative emotionality, and high attentional focus) exhibited lower total cortisol output 15 years later. In addition, greater self-regulation in childhood predicted greater use of active coping in adolescence, whereas a greater number of negative life events predicted increased use of avoidant coping in adolescence. Finally, a greater number of negative events in childhood predicted marginally lower total cortisol output, and higher levels of active coping in adolescence were associated with greater total cortisol output in young adulthood. Findings suggest that children of divorce who exhibit better self-regulation evidence lower cortisol output during a standardized psychosocial stress task relative to those who have higher impulsivity, lower attentional focus, and/or higher negative emotionality. The conceptual significance of the current findings, including the lack of evidence for hypothesized relations, methodological issues that arose, and issues in need of future research are discussed.
ContributorsHagan, Melissa (Author) / Luecken, Linda (Thesis advisor) / MacKinnon, David (Committee member) / Wolchik, Sharlene (Committee member) / Doane, Leah (Committee member) / Arizona State University (Publisher)
Created2013
Description
In order to analyze data from an instrument administered at multiple time points it is a common practice to form composites of the items at each wave and to fit a longitudinal model to the composites. The advantage of using composites of items is that smaller sample sizes are required in contrast to second order models that include the measurement and the structural relationships among the variables. However, the use of composites assumes that longitudinal measurement invariance holds; that is, it is assumed that that the relationships among the items and the latent variables remain constant over time. Previous studies conducted on latent growth models (LGM) have shown that when longitudinal metric invariance is violated, the parameter estimates are biased and that mistaken conclusions about growth can be made. The purpose of the current study was to examine the impact of non-invariant loadings and non-invariant intercepts on two longitudinal models: the LGM and the autoregressive quasi-simplex model (AR quasi-simplex). A second purpose was to determine if there are conditions in which researchers can reach adequate conclusions about stability and growth even in the presence of violations of invariance. A Monte Carlo simulation study was conducted to achieve the purposes. The method consisted of generating items under a linear curve of factors model (COFM) or under the AR quasi-simplex. Composites of the items were formed at each time point and analyzed with a linear LGM or an AR quasi-simplex model. The results showed that AR quasi-simplex model yielded biased path coefficients only in the conditions with large violations of invariance. The fit of the AR quasi-simplex was not affected by violations of invariance. In general, the growth parameter estimates of the LGM were biased under violations of invariance. Further, in the presence of non-invariant loadings the rejection rates of the hypothesis of linear growth increased as the proportion of non-invariant items and as the magnitude of violations of invariance increased. A discussion of the results and limitations of the study are provided as well as general recommendations.
ContributorsOlivera-Aguilar, Margarita (Author) / Millsap, Roger E. (Thesis advisor) / Levy, Roy (Committee member) / MacKinnon, David (Committee member) / West, Stephen G. (Committee member) / Arizona State University (Publisher)
Created2013