This collection includes most of the ASU Theses and Dissertations from 2011 to present. ASU Theses and Dissertations are available in downloadable PDF format; however, a small percentage of items are under embargo. Information about the dissertations/theses includes degree information, committee members, an abstract, supporting data or media.

In addition to the electronic theses found in the ASU Digital Repository, ASU Theses and Dissertations can be found in the ASU Library Catalog.

Dissertations and Theses granted by Arizona State University are archived and made available through a joint effort of the ASU Graduate College and the ASU Libraries. For more information or questions about this collection contact or visit the Digital Repository ETD Library Guide or contact the ASU Graduate College at gradformat@asu.edu.

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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

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
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Description
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

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
This study aims to address the deficiencies of the Marcus model of electron transfer

(ET) and then provide modifications to the model. A confirmation of the inverted energy

gap law, which is the cleanest verification so far, is presented for donor-acceptor complexes.

In addition to the macroscopic properties of the solvent, the physical

This study aims to address the deficiencies of the Marcus model of electron transfer

(ET) and then provide modifications to the model. A confirmation of the inverted energy

gap law, which is the cleanest verification so far, is presented for donor-acceptor complexes.

In addition to the macroscopic properties of the solvent, the physical properties of the solvent

are incorporated in the model via the microscopic solvation model. For the molecules

studied in this dissertation, the rate constant first increases with cooling, in contrast to the

prediction of the Arrhenius law, and then decreases at lower temperatures. Additionally,

the polarizability of solute, which was not considered in the original Marcus theory, is included

by the Q-model of ET. Through accounting for the polarizability of the reactants, the

Q-model offers an important design principle for achieving high performance solar energy

conversion materials. By means of the analytical Q-model of ET, it is shown that including

molecular polarizability of C60 affects the reorganization energy and the activation barrier

of ET reaction.

The theory and Electrochemistry of Ferredoxin and Cytochrome c are also investigated.

By providing a new formulation for reaction reorganization energy, a long-standing disconnect

between the results of atomistic simulations and cyclic voltametery experiments is

resolved. The significant role of polarizability of enzymes in reducing the activation energy

of ET is discussed. The binding/unbinding of waters to the active site of Ferredoxin leads

to non-Gaussian statistics of energy gap and result in a smaller activation energy of ET.

Furthermore, the dielectric constant of water at the interface of neutral and charged

C60 is studied. The dielectric constant is found to be in the range of 10 to 22 which is

remarkably smaller compared to bulk water( 80). Moreover, the interfacial structural

crossover and hydration thermodynamic of charged C60 in water is studied. Increasing the

charge of the C60 molecule result in a dramatic structural transition in the hydration shell,

which lead to increase in the population of dangling O-H bonds at the interface.
ContributorsWaskasi, Morteza M (Author) / Matyushov, Dmitry (Thesis advisor) / Richert, Ranko (Committee member) / Heyden, Matthias (Committee member) / Beckstein, Oliver (Committee member) / Arizona State University (Publisher)
Created2019
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Description
Since understanding the nature of proteins, it has been a long held belief that protein sequence dictated structure which then determined function. As such, all proteins contained structure and those that did not must not serve a purpose. For the last 25 years, scientists have begun to understand that disordered

Since understanding the nature of proteins, it has been a long held belief that protein sequence dictated structure which then determined function. As such, all proteins contained structure and those that did not must not serve a purpose. For the last 25 years, scientists have begun to understand that disordered proteins, lacking structure, did not lack function. Their unique ability to undergo liquid-liquid phase separation served a cellular purpose, most involving nucleic acids. As more is uncovered, these unique proteins are being used to build new systems. Phase separated disordered proteins were used to design a functional organelle using the enzyme horseradish peroxidase and its chromatic substrate ABTS. Upon doing so, it was discovered that disordered proteins are highly susceptible to chemical modification through radical reactions with tyrosine. The increased frequency of tyrosine in disordered proteins provides multiple sites of conjugation by the ABTS radical and other substrates. These modifications then alter the physical properties of the proteins. The phase separated system was also incorporated with shell proteins from bacterial microcompartments in an attempt to limit access to the droplets. Through expression with truncations of the disordered sequence, shell proteins were able to interact with the droplets. Despite the appearance of complete coatings, they were found to be permeable to their surroundings, though much more stable than uncoated droplets. Just as disordered proteins are considered outside the traditional structures, so too are many students entering higher education. Non-traditional students are becoming more prevalent in the undergraduate population, though they are woefully underrepresented in the natural sciences. The benefits these students bring to their programs is highlighted and the circumstances that drive them away from STEM is explored. Non-traditional students contribute to the diversity of the scientific population, though many pursue education in non-STEM fields. To support these students, focus is put on andragogy (the teaching of adults), rather than pedagogy (the teaching of children). Non-traditional students face isolation and discrimination that is not being addressed by higher education institutions, hindering their ability to succeed. Through infrastructure designed for adult learners, STEM fields can be diversified in non-traditional ways.
ContributorsCostantino, Michele (Author) / Ghirlanda, Giovanna (Thesis advisor) / Mills, Jeremy (Committee member) / Matyushov, Dmitry (Committee member) / Arizona State University (Publisher)
Created2024